R HIV Vaccine Safety and Adleviation of Virus Vector

a Publication of the HIV Vaccine Trials Network Volume 5, issue 1 OCTOBER, 2013 CLOSING IN ON Probing scientific questions to advance HIV vaccine development Tracey Day and Cecilia Morgan Several HVTN trials have gone beyond the standard safety and immunogenicity assessments to address important scientific questions for the field. These studies provide a means to accelerate vaccine development by obtaining critical information applicable to multiple vaccine concepts. Here, we describe some of the key scientific questions that recent HVTN studies have probed and provide a sneak peak at the emerging data. Maximizing T-cell response breadth (HVTN 083, 085) Considerable evidence indicates that HIV specific T- cell responses play a key role in controlling the levels of virus detected in the blood of infected patients. 1 Although the Merck recombinant adenovirus serotype 5 (rad5)-vectored vaccine elicited high T-cell response rates, it did not protect against infection or reduce viral loads in infected participants in the Step Study. 2,3 One possible explanation that has been postulated is that the T-cell responses elicited by this vaccine were too narrowly focused to provide adequate control of viral replication. 4-6 Few pathogens exhibit the level of genetic sequence variability that is observed in HIV strains. Eliciting immune responses capable of recognizing such a diverse range of variants is one of the most significant challenges for HIV vaccine development. Vaccines that induce greater T-cell response breadth, defined IN THIS ISSUE 11 18 22 Innovative Research Arising from HVTN Award Programs HVTN Protocols -- Enrolling or in Follow Up HVTN Efficacy Trials Results 24 35 38 Signs of the Time: Technology Updates at the HVTN The HIV Vaccine Trials Network at AIDS VACCINE 2013 HVTN Annual Network Award Winners CALENDAR [back cover]

Probing scientific questions to advance HIV vaccine development Probing scientific questions to advance HIV vaccine development as the number of HIV-specific epitopes recognized, may block viral escape pathways and lead to earlier control of replication or slower disease progression for infected individuals. Some epitopes are conserved, or shared, across many HIV variants. Increasing the number of conserved epitopes that are recognized by vaccine-induced T cells, in particular, may further optimize protection from diverse HIV variants. HVTN 083 and HVTN 085 are 2 studies that are being conducted to evaluate multiple factors that may improve the quality of vaccine elicited cellular responses. Rather than validating the specific adenoviral (Ad)-vectored products used, these trials aimed to identify general approaches that may improve the magnitude and breadth of T-cell responses induced by vaccination. Data from these studies have recently become available. HVTN 083 is a phase 1 clinical trial that evaluated prime/boost regimens comprising heterologous vectors and/or heterologous inserts as a means to improve the breadth, magnitude, and/or character of the T-cell response (Figure 1). The study was designed to answer 2 main questions: 1. Do priming and boosting with inserts containing overlapping, non-identical sequences of the same gene focus the T-cell response to conserved regions present in both inserts? 2. Does a prime/boost regimen containing heterologous vectors improve cellular immune response, compared to a regimen containing homologous vectors? To answer the first question, 2 HIV envelope glycoprotein (Env) inserts, one from clade A (Env A) and the other from clade B (Env B), were used with rad vectors in the study. T-cell responses targeting epitopes that were either shared between the Env A and Env B inserts or more generally conserved across HIV strains would theoretically recognize a larger number of distinct HIV isolates. For the second question, the study looked at vectors of different rad serotypes (rad5 and rad35), with the same Figure 1. HVTN 083: Do prime/boost regimens containing heterologous inserts or heterologous vectors enhance vaccine-induced T-cell response breadth? To answer this question, the targets of HIV Env-specific T cells elicited in each study arm were determined via epitope mapping. T cell IFN-γ/ IL-2 intracellular cytokine staining assays were performed with specimens collected 2 weeks after the final vaccination. Peripheral blood mononuclear cells were stimulated with pools of overlapping peptides spanning the Env protein sequence. Positive samples were further tested with individual peptides. In the graph on the left, the frequencies of positive samples (left panel, x-axis) are shown for each peptide relative to the corresponding Env protein sequence (left panel, y-axis). Color coded dots indicate results from each study arm, as illustrated in the study schema to the right. This figure was adapted from a slide presented by Dr. Stephen Walsh at the spring HVTN Full Group Meeting. In this preliminary analysis, it was observed that some epitopes were more frequently targeted and may represent immunodominant hotspots (for example, around residues 50 and 450). Shaded ovals highlight regions where an increase in T-cell response breadth was observed in heterologous insert groups (group B, orange dots; group E, green dots). or different inserts, compared to 2 administrations of the same rad serotype vector. Previous studies have indicated that heterologous vector prime/boost regimens result in higher magnitude T-cell responses than homologous vector regimens. 7-9 This may be due to rapid generation of anti-vector immunity following re-administration of a homologous vector. HVTN 083 enrolled 180 subjects who lacked preexisting neutralizing antibodies specific for Ad35 or Ad5 or both. The 3 vaccines used in the study (rad35 Env A, rad5 Env A, and rad5 Env B) were developed by the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID). Participants were randomized to one of 5 groups evaluating different combinations of heterologous inserts, homologous inserts, heterologous vectors, and homologous vectors administered in prime/boost regimens as indicated in Figure 1. Preliminary HVTN 083 immunogenicity data from the peak response time point were presented by Dr. Stephen Walsh at the spring HVTN Full Group Meeting in Washington, DC. All participants were exposed to Env A as part of their priming immunization and the majority developed Env A-specific T-cell responses as indicated by positive interferon-γ (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay responses to Env A peptide pools. Env B response rates were lower than Env A overall. Groups that received Env B in the boost vaccine generated the highest Env B response rates. A similar pattern was observed from IFN-γ and IL-2 intracellular cytokine staining (ICS) assays. Epitope mapping was performed to compare T-cell response breadth for each study arm. This method involves consecutive rounds of INF-γ ELISpot assays to de-convolute which peptides within a positive peptide pool are being targeted by the T cells in a specimen. Dr. Walsh presented preliminary epitope mapping results suggesting that vaccination with heterologous inserts led to somewhat of an increase in T-cell response breadth (Figure 1). An assessment of the number of shared or conserved epitopes that were targeted by each study arm has since been performed. Responses from heterologous insert groups were found to target more epitopes that were shared between the Env A and Env B inserts than the homologous insert groups. For heterologous vector groups, numbers of targeted epitopes, both insert-specific and shared, were higher overall than for homologous vector groups. Further analyses are ongoing. Neutralizing antibody responses were an exploratory endpoint in HVTN 083. It was hypothesized that if heterologous insert regimens elicited more conserved epitope responses, humoral responses could possibly focus on epitopes more vulnerable to neutralization. Dr. Walsh presented data from neutralizing antibody assays performed in TZM-bl cells in which neutralization activity was detected largely against a single tier 1 clade C isolate known to be relatively easily neutralizable (MW965.26). In contrast to the exploratory hypothesis, neutralizing antibody response rates were lower in heterologous insert groups. The preliminary findings from HVTN 083 show that prime/boost regimens containing heterologous inserts and vectors can increase breadth of T-cell responses and enhance recognition of conserved epitopes. HVTN 085 was another study evaluating parameters that may enhance vaccine-induced cellular responses. In this study, a polytopic vaccine administration (injecting a vaccine in multiple anatomical locations) was evaluated as a means to increase T-cell response magnitude or breadth (Figure 2). The rationale for this study was based on the concept that by spreading the antigenic wealth, so to speak, certain types of narrowly focused (immunodominant) T-cell responses may be decreased. As presented by Dr. Ian Frank during the spring HVTN Full Group Meeting, polytopic vaccine administration has been shown in a murine study to overcome an immunodominant response to a particular Gag epitope, thereby enhancing responses to a subdominant epitope. 10 In addition, it has been postulated that polytopic vaccine administration, which is often used to accommodate appreciable vaccine volumes in relatively smaller animals, could help explain why vaccine-induced responses are often significantly higher in non-human primates compared to humans. 2 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 3

Probing scientific questions to advance HIV vaccine development Probing scientific questions to advance HIV vaccine development The vaccine tested in HVTN 085 was a 4 component rad5-vectored vaccine developed by the VRC (VRC rad5 gag-pol, env A/B/C). The study compared 3 different administration strategies that are illustrated in Figure 2. In the first group, a combined vaccine containing all 4 vaccine components was injected in a single limb (right arm), a typical vaccine administration strategy in humans. In the 2nd group, each vaccine insert component was injected in a different limb (right arm, left arm, right thigh, left thigh). It was hypothesized that by targeting each insert to a different lymph node, this strategy would eliminate insert competition within the same lymph Figure 2. HVTN 085: Does polytopic administration improve T-cell response quality? To answer this question, T-cell responses were compared when a 4-component adenovirus-vectored vaccine was administered in the same or different limbs as shown in this illustration. Top: all 4 vaccine components were administered intramuscularly in a single injection in the right deltoid, a typical administration strategy. Bottom left: each vaccine component was administered in a different limb, a polytopic administration strategy targeting each insert to a different lymph node. Bottom right: all 4 vaccine components were combined and diluted 1:4 and administered in each of 4 limbs, a polytopic administration strategy distributing a quarter dose of all antigens over 4 lymph nodes. This figure was adapted from illustrations presented by Dr. Ian Frank at the spring HVTN Full Group Meeting. node and thereby help overcome any potential immunodominance. As in the murine study, curtailing dominant responses would be expected to increase T-cell response breadth. In the 3rd group, the combined 4-component vaccine was diluted to a 1/4 dose and equal volumes were injected in 4 different limbs. By distributing a fraction of the complete vaccine among multiple lymph nodes, this administration strategy was hypothesized to increase the magnitude of the response. To maintain the study blind by treatment group, placebo vaccinations were given in the remaining 3 limbs in the first group. Dr. Frank presented the T-cell response data (as assessed by IFN-γ/IL-2 ICS) available thus far from the primary immunogenicity timepoint. Overall, there was a trend toward increased number of responders, particularly for HIV-specific CD8 + T cells, and higher magnitude responses against some antigens in the group receiving the complete diluted vaccine in 4 limbs (Arm 3, Figure 2). A preliminary assessment of T-cell response breadth based on number of peptide pools generating a positive ICS response was also presented. A significantly higher number of peptide pools were recognized by CD8 + T cells from the group receiving the complete diluted vaccine in 4 limbs (Arm 3, Figure 2). This suggests that polytopic administration of the complete vaccine may increase breadth for CD8 + T cells. Complete epitope mapping analyses are ongoing and will allow a more thorough evaluation of how different polytopic vaccination strategies affected T-cell response breadth. Findings from HVTN 083 and HVTN 085 may be applicable to other viral vector vaccine platforms, and additional strategies for improving T-cell response breadth will be assessed in future HVTN trials. One example is HVTN 099, which is being collaboratively developed by the HVTN, NIAID, the Center for HIV/AIDS Vaccine Immunology (CHAVI), Los Alamos National Laboratory (LANL), the IPPOX Foundation in Switzerland, and the Bill and Melinda Gates Foundation. This study will compare T-cell response breadth elicited by mosaic and consensus Env immunogens designed by LANL, CHA- VI, and NIAID. 11 Together these data will serve to guide future efforts to optimize T-cell response frequency and quality, in order to maximize control of HIV replication. Effects of protein boosts (HVTN 073E and 088) The RV144 trial demonstrated for the first time that vaccination can reduce HIV infection risk in humans. 12 This trial evaluated a canarypox vector prime (ALVAC, Sanofi Pasteur) and an Env protein boost (AIDSVAX B/E, VaxGen) vaccine regimen in Thailand. The study reported an estimated vaccine efficacy of 31.2% and although only partial efficacy was observed, this result invigorated the field. In a subsequent immune correlates analysis, immune responses correlating with infection risk were identified. 13 Chief among these were Env-specific antibody responses that correlated with decreased risk of HIV infection. These findings resulted in a surge of interest in vaccine-induced antibody responses. One way to promote antibody responses is through protein vaccine boost immunizations, such as the Env protein boost administered as part of the RV144 trial regimen. To begin further exploration of the effects of protein boosts, HVTN researchers conducted 2 studies in which Env protein boosts were administered to study subjects that had been primed as part of previous or ongoing HVTN trials. One of these studies, HVTN 073E, was an extension of HVTN 073/SAAVI 102. HVTN 073/SAAVI 102 was a phase 1 trial conducted in South Africa and the United States. The trial evaluated a DNA vaccine (SAAVI DNA C2) prime followed by a modified vaccinia Ankara (MVA) viral vector vaccine (SAAVI MVA C) boost. Although this regimen differed from RV144, both regimens had in common the use of a poxvirus vector vaccine. Administering an Env protein boost to HVTN 073/SAAVI 102 participants was an efficient way to examine how a protein boost could enhance antibody responses following a viral vector prime. Thus, a study extension (HVTN 073E) was developed to evaluate the safety and immunogenicity of Novartis Sub C gp140 vaccine with MF59 adjuvant as a late boost following a DNA/MVA prime/boost regimen. The first protein dose was administered around 2 years 4 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 5

Probing scientific questions to advance HIV vaccine development Probing scientific questions to advance HIV vaccine development after the participant s first (DNA or placebo) injection in HVTN 073/SAAVI 102. A second protein dose was given 3 months after the first. HVTN 073E enrolled 27 participants and data available thus far include neutralizing antibody responses from specimens collected 2 weeks after each protein administration. Preliminary results indicate that boosting with protein improves neutralizing antibody responses for DNA/MVA primed subjects. Neutralizing antibody response rates were significantly higher in those receiving the DNA/MVA prime and gp140 boost than in those who received the DNA/MVA prime and were not boosted with gp140. This was true for neutralization assays performed in both TZM-bl and A3R5 cells, in which neutralizing activity was detected against tier 1 and tier 2 viruses. Notably, neutralizing antibody responses, which were not detected in the main HVTN 073/SAAVI 102 dataset, were detected after a single protein boost in the study extension. In the absence of priming, several protein administrations are typically required to elicit neutralizing antibody responses. That these responses were detected after a single dose indicates efficient priming by the DNA/MVA regimen and points to protein boosts as an effective way to boost such responses. Whether binding antibody responses were also enhanced by the protein boosts will also be of interest. These analyses, as well as T-cell response assessments, are ongoing. HVTN 073E represents the first time that a protein was administered as a boost to a poxvirus vector vaccine in South Africa, setting the stage for further exploration of pox/protein combinations in the region. HVTN 088 is another study investigating whether boosting previously primed study subjects with protein could enhance antibody responses. This time the boosting occurred after a significant rest of 5-7 years or more. Providing a longer rest was considered a potential way to allow more time for B cell maturation and thus, possibly more effective antibodies to develop. In addition, HVTN 088 examined whether boosting with an immunogen specific for a different virus clade would result in broadening the virus cross-reactivity of the boosted immune responses. In this case, participants were previously primed with clade B immunogens and, as part of HVTN 088, they would be boosted with a clade C Env protein vaccine, Sub C gp140/mf59, the same vaccine used in HVTN 073E. The concept of using a divergent protein boost immunogen to broaden primed antibody responses was based on promising results from an influenza vaccine study. In that study, priming and boosting with hemagglutinin antigens from different influenza strains resulted in the induction of high titer antibody responses that were cross-reactive for multiple virus strains. 14 HVTN 088 aimed to test whether this would hold true for HIV Env antigens as well. Some of the HVTN 088 participants came from older studies containing clade B protein immunogens. These studies were conducted by the HVTN predecessor network, the AIDS Vaccine Evaluation Group (AVEG). The majority of participants, however, were primed as part of HVTN 049, a protocol that tested a clade B gag, env DNA vaccine (DNA/polylactide coglycolide microparticles, Chiron) followed by a clade B Env protein vaccine (clade B recombinant gp140 protein with MF59, Novartis, formerly Chiron). This regimen in HVTN 049 elicited good titers of neutralizing antibodies in 100% of recipients. But, virus cross-reactive neutralization breadth, as measured by the TZM-bl assay, was limited. An update on HVTN 088 results, based on the data available thus far, was presented by Dr. Paul Spearman at the spring HVTN Full Group Meeting. As presented by Dr. Spearman, even before boosting, a significant portion of HVTN 049 participants had detectable T-cell and antibody responses to the HVTN 049 clade B HIV antigens. This indicates that the HVTN 049 regimen elicited memory responses that could persist for at least 5-7 years. Administering the clade C protein vaccine resulted in a rapid and strong boosting of these responses after a single dose with little change after the second dose. Neutralizing antibody response data obtained in both TZM-bl and A3R5 assays indicated that the boosted neutralizing antibody responses were only slightly higher for clade B viruses than the HVTN 049 peak response levels. And surprisingly, even after the 2nd boost with a clade C protein, the neutralizing antibody responses for clade C viruses were lower, rather than higher, than the peak HVTN 049 levels. Thus, in contrast to the hypothesis that priming and boosting with divergent antigens could broaden neutralizing antibody responses, based on the HVTN 088 data thus far, response breadth seemed to decrease. These unexpected results inform researchers that increasing neutralizing antibody response breadth is complex, and highlight a need for further investigation. Detailed B-cell analyses of the HVTN 088 specimens are planned that may help investigators better understand these results. In addition, mucosal immune response analyses are ongoing, which may also provide clues as to how boosting with a divergent protein immunogen may affect antibody responses at mucosal sites, as compared to the responses detected in blood. Why might clade C neutralizing antibody responses not improve with a clade C antigen boost? This remains unknown, but as explained by Dr. Spearman during his presentation, these findings may present evidence for a theory known as original antigenic sin. This theory is based on the observation that in some cases, boosting with a heterologous antigen can result in a dampening of antibody responses to the divergent antigen. The hypothesis would be that the antibody responses generated against the priming clade B antigen dominated and interfered with responses to the clade C boost antigen. If this were indeed the case for HVTN 088, one would expect that peak clade C neutralizing antibody responses would be higher in subjects who received the clade C protein without being primed with the clade B antigens. Such a difference was not observed; however, it is possible that this was because this group received only 2 protein doses and, although response rates were steadily increasing, prior studies have indicated that 3 protein administrations are often required for peak responses. Taken together, the preliminary results from HVTN 073E and HVTN 088 indicate that antibody responses can be enhanced by protein boost administrations. Ongoing analyses will provide a more complete picture of the specific character and durability of these responses, both systemically and within mucosal tissues. Although some of these findings were unexpected, they serve to reveal the complexity of heterologous vaccination strategies and highlight the need for further studies, like these, to improve our understanding of how best to employ such approaches. Going forward, additional ongoing and future studies will further address how to utilize protein vaccines to elicit optimal responses. For more information, see the HVTN Protocols -- Enrolling or in Follow Up table in this issue (pages 18-21), specifically the descriptions of HVTN 086, 096, and 097. Exploring heterologous viral vector prime/boost regimens (HVTN 077 and 078) The use of viral vectors as HIV vaccines is attractive, because they can induce strong T-cell and antibody responses. Two recent phase 1b studies, HVTN 077 and 078, have explored using heterologous viral vector primes and boosts and factors impacting immune responses. Data emerging from these studies are revealing optimal strategies for employing viral vectors to induce robust T-cell and antibody responses. HVTN 078 was a phase 1b study that addressed two important questions regarding the optimal way to combine two different viral vectors in a prime/boost regimen: 1. How does administration order impact responses when 2 different viral vector vaccines are used? 2. What dose of a strongly immunogenic prime works best when paired with a strongly immunogenic boost? Animal studies have shown that, for heterologous viral vector regimens, order can influence the character of the responses to specific inserts. 15 Therefore, HVTN 078 compared immune responses when rad5 was used as a prime followed by a NYVAC boost to the reverse order (a NYVAC prime and a rad5 boost). In addition, 3 different rad5 doses (10 8, 10 9, and 10 10 plaque forming units) were tested to evaluate whether weak, intermediate, or strong priming produced the best responses preceding a NYVAC boost. 6 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 7

Probing scientific questions to advance HIV vaccine development Probing scientific questions to advance HIV vaccine development The study enrolled 80 Ad5 neutralizing antibody seronegative circumcised men in Switzerland. Primary immunogenicity data was assessed 2 weeks after the final vaccination. T-cell response data from HVTN 078 were presented at the AIDS Vaccine 2012 conference in an oral presentation by Dr. Pierre-Alexandre Bart and antibody response data were presented in a poster by Dr. David Montefiori. 16,17 Higher CD4 + T-cell response rates, as assessed via IFN-γ/IL-2 ICS, were observed when rad5 was used as a prime and NYVAC was used as a boost. A similar trend was observed for CD8 + T-cell responses. Different doses of rad5 used for priming did not significantly affect T-cell response frequencies or magnitude. Further analyses of T-cell response characteristics, including polyfunctionality regarding cytokine production, are ongoing. An assessment of mucosal responses is also planned. For humoral responses, the highest binding and neutralizing antibody response rates were observed when recipients were primed with the highest rad5 dose and boosted with NYVAC. Among positive responders, the same effect was observed for response magnitudes. In comparison with other rad5 studies, as noted by Dr. Montefiori, neutralizing capacity against tier 1 viruses from rad5/nyvac was generally better than has been observed with DNA/rAd5 regimens (eg, the regimen evaluated in HVTN 204, Figure 3). 17 Overall, HVTN 078 demonstrated a significant impact of vector order in heterologous vector regimens, with rad5 priming and NYVAC boost eliciting higher T-cell and antibody responses. The highest rad5 priming dose induced the strongest antibody responses, and no dose response was observed for T-cell responses. Thus, these data support the concept of a employing a strong priming immunogen as a potential means to strongly elicit both cellular and humoral responses. One potential limitation to using some viral vectors, however, is the presence of pre-existing immunity from exposure to the wild type virus that can then direct immune responses against the viral vector vaccine. The estimated seroprevalence of Ad5 neutralizing antibodies is 37-99%, and is particularly higher in some of the same regions where HIV incidence is high. For example, in South Africa this seroprevalence has been reported at 88 90%; whereas the neutralizing antibody seroprevalence to other Ad serotypes, such as Ad35, is substantially lower. 18,19 HVTN 077 is a phase 1b trial investigating whether preexisting humoral immunity to Ad5 could be circumvented using an alternative adenoviral serotype vector, Ad35. This study tested a rad35-vectored vaccine in combination with a rad5 or a DNA vaccine, all developed by the VRC and contained HIV clade A Env inserts. The study was designed to address the following questions: 1. How does rad35 perform compared to DNA as a prime for a viral vector with higher pre-existing seroprevalence? 2. How does rad35 perform as compared to rad5 as a boost to DNA? 3. What is the effect of pre-existing neutralizing antibodies to one virus serotype on a regimen that includes a DNA prime and a boost with a viral vector of a different serotype? The answers to these questions would provide specific clues for circumventing any potential negative effects of pre-existing vector immunity. The study was conducted in the US and enrolled 192 participants. Absence of detectable Ad35-specific neutralizing antibodies was required for all subjects. Data collected 2 weeks after the last vaccination was presented by Dr. Jonathan Fuchs at the HVTN Full Group Meeting held in October, 2012 and at the AIDS Vaccine 2012 conference. 20 Each regimen evaluated in HVTN 077 elicited high frequency and magnitude binding antibody responses as determined from validated binding antibody multiplex assays (BAMA). Despite the fact that all vaccines contained only Env inserts from HIV clade A, positive BAMA results were observed against Env antigens for Figure 3. Comparison of neutralizing antibody responses in HVTN 078 and HVTN 204. Magnitude-breadth (M-B) curves, as shown here, integrate data on the neutralizing antibody response magnitude and breadth, 2 important criteria for evaluating vaccine-induced humoral responses. Neutralization response magnitude refers to the quantity of neutralizing antibodies against a single virus strain in a serum sample. This value is determined by assessing the ability of serum antibodies to block viral entry into cells in vitro. Results are plotted as the reciprocal titer of sera required to reduce the number of infectious viral particles by 50% (infectious dose 50 or ID 50). Neutralization breadth refers to the extent by which serum antibodies neutralize multiple virus strains. This value is expressed as a positive response rate indicating the fraction of virus strains from a panel that are neutralized for a given ID 50 titer. Here, M-B curves comparing neutralizing antibody responses in HVTN 078 and HVTN 204 are shown. HVTN 078 data are from the group of subjects who received only placebo (Placebo 078, white) and the subjects who received the highest priming rad5 vaccine dose (10 10 PFU) followed by 2 NYVAC boost administrations (078 rad5/nyvac, red). HVTN 204 data are from subjects who received only placebo (Placebo 204, pink) and subjects who received 3 DNA priming vaccinations followed by a rad5 (10 10 PFU dose) boost (204 DNA/rAd5, blue). Neutralization results are shown for a panel of 4 virus strains (MN.3, SF162.LS, Bal.26, and MW965.26) using TZM-bl cells. The neutralization response magnitude was determined from ID 50 values. Thin lines represent estimated subject-specific responses and solid areas represent group averages. A comparison of group averages indicates that neutralizing antibody responses in the above-mentioned treatment group of HVTN 078 were significantly stronger than responses in the HVTN 204 treatment group. This graph was adapted from a poster presented by Dr. David Montefiori at the AIDS Vaccine 2012 conference. 17 8 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 9

Probing scientific questions to advance HIV vaccine development clades B and C, as well as clade A. Furthermore, high levels of V1/V2-specific IgG binding antibody responses that were correlated with reduced HIV infection risk in the RV144 trial were also detected. 13 No significant differences were found between groups for any of the antibody responses evaluated thus far. HIV-specific CD4 + and CD8 + T-cell responses were also potently induced by all regimens, with no significant differences in response rates or response magnitude between groups. A non-significant trend toward improved CD4 + T-cell responses with DNA priming, as compared to rad35 priming, was noted. In addition, somewhat reduced, but not statistically significant, CD4 + T-cell responses to DNA/rAd35 were observed in the Ad5 seropositive group, indicating a potential hint of some cross reactivity between pre-existing immunity to one vector on a vaccine from another serotype. Taken together, the study findings address several questions regarding the use of vectors made from viruses that are less prevalent. Overall, the performance of the rad35-based vector was comparable to rad5. In addition, the rad35-vector was capable of inducing potent cellular and humoral responses even among individuals harboring pre-existing immunity to Ad5. Summary In accordance with its mission, the HVTN strives to fully characterize the safety, immunogenicity, and efficacy of HIV vaccine candidates. The studies presented above also sought to answer specific scientific questions regarding optimization of vaccine responses. Data emerging from these studies point to a variety of factors impacting vaccine response magnitude and breadth. This information may be applicable for multiple vaccine platforms, and serve to guide the field toward our goal of developing a safe and globally effective vaccine to prevent HIV infection. Acknowledgements We thank HVTN 073E, 077, 078, 083, 085, and 088 protocol team members, in particular Mary Allen, Pierre-Alexandre Bart, Carter Bentley, Stephen De Rosa, Marnie Elizaga, Ian Frank, Jonathan Fuchs, Yunda Huang, Nidhi Kochar, David Montefiori, Georgia Tomaras, and Stephen Walsh for their help in preparing this article. In addition, we thank Allan decamp, Lisa Donohue, Greg Finak, Nicole Frahm, and David Friedrich. Tracey Day is HVTN Senior Science Writer, Cecilia Morgan is HVTN Associate Director, Scientific Development. References 1. Deeks SG, Walker BD. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity. 2007;27(3):406-416. 2. Buchbinder SP, Mehrotra DV, Duerr A, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet. 2008;372(9653):1881-1893. 3. Fitzgerald DW, Janes H, Robertson M, et al. An Ad5-vectored HIV-1 vaccine elicits cell-mediated immunity but does not affect disease progression in HIV-1-infected male subjects: results from a randomized placebo-controlled trial (the Step Study). J Infect Dis. 2011;203(6):765-772. 4. McElrath MJ, De Rosa S, Moodie Z, et al. HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis. Lancet. 2008; 372(9653):1894-905. 5. Janes H, Friedrich DP, Krambrink A, et al. Vaccineinduced Gag-specific T cells are associated with reduced viremia after HIV infection. J Infect Dis. 2013;Aug 13. [Epub ahead of print]. 6. Frahm N. Defining the targets of HIV-specific T-cell responses (epitope mapping). HVTNews. 2011;3(1):10-11. 7. Goepfert PA, Elizaga ML, Sato A, et al. Phase 1 safety and immunogenicity testing of DNA and recombinant modified vaccinia Ankara vaccines expressing HIV-1 virus-like particles. J Infect Dis. 2011;203(5):610-619. 8. Day T, Metch B, Frahm N, Morgan C. Immunogenicity data patterns emerging from cross trial comparisons. HVTNews. 2013;4(2):1-8. 9. Keefer MC, Frey SE, Elizaga M, et al. A phase I trial of preventive HIV vaccination with heterologous poxviral-vectors containing matching HIV-1 inserts in healthy HIV-uninfected subjects. Vaccine. 2011;29(10):1948-1958. 10. Liu J, Ewald BA, Lynch DM, Nanda A, Sumida SM, Barouch DH. Modulation of DNA vaccineelicited CD8+ T-lymphocyte epitope immunodominance hierarchies. J Virol. 2006;80(24):11991-11997. 11. Day T, Morgan C, Kublin JG. Will mosaic vaccine immunogens expand immune response breadth to rival HIV-1 strain diversity? Clinical Investigation. 2013;3(5):413-415. 12. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361(23):2209-2220. 13. Haynes BF, Gilbert PB, McElrath MJ, et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med. 2012;366(14):1275-1286. 14. Galli G, Hancock K, Hoschler K, et al. Fast rise of broadly cross-reactive antibodies after boosting longlived human memory B cells primed by an MF59 adjuvanted prepandemic vaccine. Proc Natl Acad Sci USA. 2009;106(19):7962-7967. Innovative Research Arising from HVTN Award Programs Tracey Day HVTN award programs are designed to foster innovation, diversity, and collaboration in support of HIV vaccine development. Research conducted in conjunction with 3 different award programs was presented during a plenary session of the spring 2013 HVTN Full Group Meeting, held in Washington, DC. This invigorating session covered a wide range of novel and pertinent HIV vaccine research, which is summarized below. 15. Casimiro DR, Bett AJ, Fu TM, et al. Heterologous human immunodeficiency virus type 1 primingboosting immunization strategies involving replication-defective adenovirus and poxvirus vaccine vectors. J Virol. 2004;78(20):11434-11438. 16. Bart P, Huang Y, Frahm N, et al. rad5 prime/ NYVAC-B boost regimen is superior to NYVAC-B prime/rad5 boost regimen for both response rates and magnitude of CD4 and CD8 T-Cell responses. Retrovirology. 2012;9(Suppl 2):O72 17. Montefiori D, Huang Y, Karuna M, et al. rad5/ NYVAC-B is superior to NYVAC-B/rAd5 and is dependent on rad5 dose for neutralizing antibody responses against HIV-1. Retrovirology. 2012; 9(Suppl 2):P132. 18. Barouch DH, Kik SV, Weverling GJ, et al. International seroepidemiology of adenovirus serotypes 5, 26, 35, and 48 in pediatric and adult populations. Vaccine. 2011;29(32):5203-5209. 19. Morgan C, Bailer R, Metch B, et al. International seroprevalence of neutralizing antibodies against adenovirus serotypes 5 and 35. Presented at: AIDS Vaccine 2005; Sept 6-9, 2005; Montreal, Canada. 20. Fuchs J, Morgan C, Bart P, et al. DNA and recombinant adenovirus serotype 35 and 5 preventive HIV-1 vaccines with Env A inserts elicit cross-clade binding and V1V2 antibodies. Retrovirology. 2012;9(Suppl 2):P136. HVTN Initiative Program The HVTN Initiative Program (HIP) is a new award program supporting innovative HVTN investigatordriven research. The aim is to provide HVTN-procured specimens, clinical, laboratory, and/or behavioral data, and funds for projects addressing scientific questions that support the HVTN research agenda. Winning proposals from this inaugural cohort sought to analyze vaccine 10 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 11

Innovative Research Arising from HVTN Award Programs Innovative Research Arising from HVTN Award Programs Tracking development of the HIV-specific T helper cell responses Given the evidence that HIV-specific antibodies may decrease HIV infection risk, understanding how HIVspecific CD4 + T cells provide help for B-cell responses is of great interest. 5 To gain insight into how HIV-specific T helper cell responses evolve during an immunization series and to identify responses correlating with viral control, Dr. Mark Pilkinton and Dr. Spyros Kalams are directly comparing the CD4 + T-cell receptor repertoires in HIV controllers and HIV vaccine recipients. A hypothesis of the study is that breadth of CD4 + T-cell receptor repertoires may be a marker of a successful immune response. Thus far, a pilot study analyzing the T-cell receptor beta chain sequences of sorted HIVspecific CD4 + T cells in 2 HIV controller subjects has been conducted. HIV-specific CD4 + T cells were isolated using fluorescence activated cell sorting based on either surface activation marker expression (CD69 and CD25) or proliferation capacity upon HIV-specific peptide (Gag and Pol) stimulation. Cells were further sorted into naïve, central memory, or effector memory populations as determined from CD45RO and CCR7 expression. T-cell receptor beta chain sequences from each of these sorted populations were determined using multiplex PCR amplification and deep sequencing methods. This approach generated a large number (typically 1000 100,000) of unique sequences from most of the sorted populations. In comparing the sequences identified in each Dr. Mark Pilkinton memory CD4 + T cell subpopuinduced B- and T-cell response repertoires, and to evaluate biomarkers of response longevity. The conference session presentations provided the Network with a first glimpse of the novel research funded by this program. Specificity and function of vaccine-induced antibodies Advances in recombinant B-cell technology have made it possible to define vaccine-induced antibody repertoires in greater detail than ever before. An in-depth analysis of memory B-cell responses elicited by HIV immunogens is being conducted by Dr. Wilton Williams. In this study, HIV-specific memory B cells from HVTN 204 and HVTN 082 serum samples have been examined on a single cell level. These trials administered a DNA prime and recombinant adenovirus serotype 5 (rad5) boost vaccine regimen containing inserts from HIV clades A, B, and C (gag-pol B, env A/B/C). 1 Using specimens collected 4 weeks after the last vaccination, HIV envelope glycoprotein (Env)- specific memory B cells were captured via antigenspecific B-cell fluorescence-activated cell sorting using Group M consensus and vaccine-matched Env oligomeric proteins. Monoclonal antibodies were investigated from clonal memory B-cell cultures established from 8 trial specimens and characterized for binding specificity and functional profile. Over 90% of the Env-specific antibodies isolated reacted with the gp41 rather than the gp120 subunit of Env. The antibodies predominantly utilized immunoglobulin variable gene subfamily VH1-69 allele. In addition, these antibodies were found to be polyreactive, exhibiting binding not just to Env, but to several other antigens including self antigens and gut flora. Similar properties have been described for gp41- specific antibodies generated in acutely HIV infected patients. 2 These findings are consistent with the hypothesis that both HIV infection and vaccination with the DNA/rAd5 regimen may induce the expansion of preexisting B-cell precursors that crossreact with the Env antigen. Expansion of a cross reactive memory response generated by non-hiv antigens could explain why Dr. Wilton Williams Env-specific antibodies are often not protective, and may represent an immune evasion strategy employed by HIV. Future studies are planned to investigate this idea further using the Env gp140 immunogen in gnotobiotic mice to examine whether the absence of gut flora will result in a less gp41-dominant response to the vaccine. Biomarkers for predicting vaccine response durability Long-lived immune responses are necessary to provide durable immunity, however currently there is neither a means to predict whether vaccine-induced responses will last nor an understanding of how to generate lasting responses. To investigate how programmed cell death, or apoptosis, of B cells may contribute to waning antibody responses, Dr. Sonya Heath is examining whether markers of apoptosis and cell survival correlate with vaccine induced B-cell response durability in HVTN 065/205 and HVTN 204. HVTN 065 and 205 administered a homologous modified vaccinia Ankara (MVA) viral vector vaccine and a heterologous DNA/MVA prime/boost regimen, whereas HVTN 204 administered the DNA/ rad5 prime/boost regimen described above. B cells from peripheral blood mononuclear cell (PBMC) samples taken after the prime, after the boost, and 6 months after the last vaccination have been analyzed in this study. Flow cytometry was used to characterize memory B cell surface marker phenotype and expression of the proapoptotic marker, cleaved caspase-3, and a prosurvival marker, Bcl-2. Results thus far indicate that high expression of cleaved caspase-3 (proapoptotic) on memory B cells early after priming correlate with a decrease in memory B cell frequencies at 6 months post boost vaccination. In contrast, prevalence of Bcl-2 (prosurvival) expressing memory B cells after priming was associated with maintenance of memory B cell frequencies at 6 months post boost. The data presented by Dr. Heath demonstrate that biomarkers of cell death and survival may be assessed in vaccine trials. Preliminary results also indicated that differences may be detected across trials, Dr. Sonya Heath for example, Bcl-2 (prosurvival) expression was higher in HVTN 205 than HVTN 204 throughout the vaccination schedule. Next steps will include unblinding of vaccine and placebo specimens and correlating these results with antibody responses to determine whether these markers are predictive for antibody response longevity. A long term goal of this study is to define a phenotypic signature of long-lived vaccineinduced B cells. Comparing B-cell profiles in high vs. low risk populations There is evidence that HIV vaccines tested in efficacy trials thus far may have been less effective in groups at high risk for HIV infection than in low risk subjects. 3 Reasons for this remain unknown, but it has been suggested that high risk behavior, such as injection drug use and high risk sexual activity, can alter an individual s immune system properties in ways that result in suboptimal responses to vaccination. Dr. James Kobie To identify what differences may exist in the immune profiles of high risk populations, Dr. James Kobie is comparing the B cell compartment profiles of HVTN 203 participants with high risk and low risk behavior. HVTN 203 evaluated the immunogenicity of ALVAC and AIDVAX B/B combination regimens. 4 To discern potential alterations in B cell homeostasis, samples from 3 months after the last vaccination were subjected to a comprehensive flow cytometry-based phenotypic analysis of global B-cell populations. Preliminary results from bulk B-cell analyses indicate an increased prevalence of memory and activated B cells in high risk as compared to low risk subjects. High risk subjects also had higher frequencies of B cells specific for the Env immunogen (gp120 MN), however, these B cells also reacted with several variable loop deleted Env variants, suggesting a potential for polyreactivity. These observations point to a potential bias toward short-lived or exhausted phenotypes among bulk and Env-specific B cells in high risk subjects. Results from this ongoing study suggest that B cell homeostasis and Env-specific B-cell responses may be altered in high risk subjects, and indicate a need to further investigate immune profiles in this population. Next steps will include linking B cell memory profiles to other immunogenicity data from HVTN 203. In addition, a complete immunoglobulin repertoire analysis and characterization of Env-specific monoclonal antibodies is planned, to investigate the origin of Env-specific B cells and evaluate their potential to give rise to neutralizing antibodies. 12 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 13

Innovative Research Arising from HVTN Award Programs Innovative Research Arising from HVTN Award Programs lation, it was found that HIV-specific T-cell receptors from HIV controller subjects can be localized to specific memory compartments and that a given sequence may exist in multiple compartments (ie, central and effector memory). The next step will be to perform this analysis for HVTN 080 HIV vaccine recipients and compare the results with those found for HIV controllers. HVTN 080 evaluated a DNA vaccine (PENNVAX TM -B) delivered via intramuscular electroporation in combination with a DNA plasmid encoding IL-12 (GENEVAX TM IL-12). 6 Specimens from 2 weeks post final vaccination will be used initially. A longitudinal evaluation of CD4 + T-cell receptor repertoires is planned using prevaccination and post-2nd vaccination specimens. The objective of this proof of concept study is to determine the feasibility of performing such in depth analyses as a means to evaluate quality of vaccine-induced T helper cell responses and their impact on B-cell responses. HVTN Research and Mentorship Program The HVTN Research and Mentorship Program (RAMP) aims to attract and retain HIV vaccine researchers from underrepresented communities. The program links Black and Latino/a medical students with HVTN affiliated investigators, and sponsors short term research projects on topics aligned with HVTN research goals. Topics may focus on one of many HIV vaccine research areas from basic science to clinical to social/ behavioral aspects. The RAMP cohort presenting at the spring conference reported on their work addressing different challenges for participant recruitment and retention in HIV vaccine trials. Testing a long-chain peer referral recruitment method Black men who have sex with men (MSM) and male to female transgender women (TW) are 2 groups that are disproportionately affected by the US HIV/AIDS epidemic and yet are underrepresented in HIV vaccine trials. New recruitment approaches are needed to ensure that sufficient efficacy data are collected for populations in need of a vaccine. Long-chain peer referral is a recruitment method that has previously been effective in recruiting hard to reach populations. Angela Coombs conducted a mixed methods study to evaluate the feasibility of this approach to recruit black MSM and TW for HIV vaccine trials in San Francisco. To implement this approach, each person screened for the study was offered the opportunity to recruit 5-7 peers via a confidential coupon referral system. Formative qualitative work was performed in which several significant barriers and some motivators to HIV vaccine trial participation were identified. A key finding was that unclear eligibility criteria could result in skepticism around the trials. In terms of number of participants enrolled in a vaccine trial, this approach had limited success. Although a large number of initial seed participants were enlisted, the long chains of peer referral were not propagated. It was suggested that, unlike other HIV prevention studies that have used this approach, vaccine trials require longer term participation and also involve delivery of experimental products, which pose significant challenges. Despite the limited success of long chain peer referral observed Angela Coombs in this study, it was concluded that adaptations could be made to better accommodate the challenges inherent in vaccine trial recruitment. A modification was proposed involving 2 stage processes. In the first stage, all black MSM and TW could be recruited for multiple studies. A second stage would then recruit for specific vaccine trials among this larger pool of participants. Embedding this recruitment approach within a broad HIV vaccine trial education effort in the Black community was also recommended. Factors impacting Atlanta-area recruitment of Blacks Tequilla Pryor s project addressed the problem of the HIV/AIDS epidemic in the state of Georgia, which is ranked 5th in the US for new HIV infections, with the majority occurring in Blacks. The objective of her study was to examine cultural, spiritual, and vaccine-related factors impacting the recruitment of Blacks into HIV vaccine trials. Data were collected using semistructured focus groups with Black men and women from the Atlanta metropolitan area. Focus groups were conducted and transcriptions were coded for themes and subthemes. Demographic data were obtained from a questionnaire. Highlights from the focus group domains include the impression that the severity of the HIV/AIDS epidemic has decreased, and the continued impact of negative stigma. Cultural factors affecting recruitment were iden- tified, including a longstanding mistrust of the medical/ scientific community, lack of knowledge of HIV-related topics, and the absence of a sense of community among Blacks. Spirituality was not found to significantly affect recruitment, however several Tequilla Pryor vaccine-related factors were. These included a fear that the vaccine contains HIV, as well as general fears about side effects, complications, and safety. Participants also made suggestions for increasing the enrollment of Blacks in clinical research. Across all focus groups, similar ideas were based on providing a fun and consistent presence in the community through family-oriented community events, outreach, and social media. These findings underscore the need to persistently engage the communities most affected by the epidemic, in order to build trust and understanding regarding clinical research in general and PROGRAM NAME HOME INSTITUTION NHP ESI Carolina Herrera Imperial College, London NHP ESI Lu-Ann Pozzi Boston Children's Hospital RAMP Angela Coombs Tufts University School of Medicine RAMP Tequilla Pryor Georgia Health Sciences University RAMP HIP Aisha Scherr- Williams Spyros Kalams (Research presented by Mark Pilkinton) Keck School of Medicine of the University of Southern California HIP Sonya Heath University of Alabama at Birmingham HIP Wilton Williams Duke Human Vaccine Institute HIP James Kobie University of Rochester PROJECT LOCATION St. George's, University of London New England Primate Research Center San Francisco Department of Public Health HIV vaccine research in particular. Barriers to HIV testing and trial recruitment in Lima Studies indicate a high HIV prevalence among MSM and TW in Lima, Peru. Aisha Scherr-Williams s project focused on understanding barriers to HIV testing in these populations. Because HIV testing is frequently the entry point to treatment and preventative services, this knowledge may promote access to such services. In addition, information regarding successful and unsuccessful strategies for increasing HIV testing among MSM and TW will facilitate future recruitment of these high risk individuals into HIV vaccine efficacy trials. As a secondary analysis of a test and treat study, data was collected from 3 in-depth interviews and 2 focus groups involving HIV negative MSM and TW participants. Qualitative data was analyzed using grounded theory in which transcript codes were not prespecified, but rather were created as themes emerged from the data. Several key operational and psychosocial barriers that may limit HIV SCHOLAR MENTORS Jerome Kim and Ronald Veazey Xu Yu and Amitinder Kaur Jonathan Fuchs and Michele Andrasik PROJECT TITLE Use of Tissue Explants to Evaluate Mucosal Immune Response in NHPs and Humans An In Vivo Cytolytic CD8 + T Lymphocyte Assay for Evaluating AIDS Vaccine Efficacy Assessing the Feasibility of Long-Chain Referral for the Recruitment of Black MSM and Black Transwomen in HIV Vaccine Studies Atlanta Mark Mulligan Investigating the Motivators and Barriers to Recruitment and Retention of African Americans in Atlanta-based HIV Vaccine Trials IMPACTA, Lima Jorge Sanchez, Patricia Segura, and Jonathan Fuchs Short Message Services as an HIV Vaccine Recruitment Technique Vanderbilt University Vanderbilt University N/A Detailed Characterization of CD4 T Helper Function and T-cell Receptor Repertoire in HIV Vaccine Recipients University of Alabama at Birmingham Duke Human Vaccine Institute University of Rochester N/A N/A N/A Apoptosis of HIV Vaccine Elicited B Cell Responses as a Marker of Vaccine Durability Characterization of the Memory B Cell and Plasma Cell Repertoires with Functional Analysis of the Antibodies Generated in Response to a HIV Envelope DNA Prime and rad5 Vector Boost Vaccination Regimen Impact of High-risk Behavior on the Composition and Engagement of the HIV Specific B cell Repertoire 14 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 15

Innovative Research Arising from HVTN Award Programs Innovative Research Arising from HVTN Award Programs testing were identified. Operational barriers included clinic hours, location, and wait times. Concern over privacy and volume of blood draws was also reported. Both personal and public negative stigma-related fears were identified as significant barriers for HIV testing. In addition, several participants described experiences in which they perceived discrimination, for example being mistreated by medical providers at testing sites. Using peer outreach workers was highly recommended by study participants because they are seen as friends who can help guide individuals through the testing process, providing education and reducing discrimination at testing sites. Addressing operational barriers such as clinic hours and test costs was also suggested. It was noted that reducing discrimination and stigma is more challenging; however several approaches to address these issues were mentioned, for example providing sensitivity training to clinic staff, and possibly carrying out campaigns designed to promote communities acceptance of their MSM and TW members. This study identified multiple important operational and psychosocial barriers that may limit HIV testing among MSM and TW in Lima. Addressing barriers identified in this study will benefit MSM and TW, and because similar barriers may also exist for vaccine trial recruitment, working to alleviate them will facilitate inclusion of Peruvian MSM and TW into future HIV vaccine efficacy trials. Aisha Scherr-Williams Early Stage Investigator Program The Non-human Primate (NHP) Early Stage Investigator (ESI) Scholar Program funds pilot studies to advance NHP models for HIV vaccine research. This initiative was collaboratively developed by the HVTN, the National Institute of Allergy and Infectious Diseases, the Center for HIV/AIDS Vaccine Immunology, and the Global HIV Vaccine Enterprise to support high priority preclinical NHP research and provide opportunities to promising ESIs in the field. At the spring conference, 2 novel NHP assays designed to improve preclinical assessment of HIV vaccine candidates were presented by recent NHP ESI award recipients. Evaluating vaccine-induced cytotoxic killing in vivo Dr. Lu-Ann Pozzi s project sought to develop an improved NHP assay for assessing the quality of vaccine induced CD8 + T-cell responses. This work addresses the problem that although CD8 + cytolytic T cells (CTL) are known to contribute to viral control, available assays do not predict CTL-mediated HIV/SIV protection. To directly measure CTL killing capacity in vivo, SIV peptide-loaded-and-labeled target cells were prepared and injected into rhesus macaques. After a set time, the fraction of target cells remaining was determined via flow cytometry of blood samples and used to calculate the percent killing that occurred in vivo. The assay was used to compare antigen-specific in vivo CTL killing in 2 NHP SIV challenge studies: one in which animals were administered a candidate prime/boost vaccine regimen and another in which an attenuated SIV (SIVΔnef ) strain was administered. Target cells were cleared more rapidly both after vaccination and challenge in SIVΔnef recipients than in those receiving the candidate vaccine. The enhanced CTL activity, as detected in the in vivo CTL assay, did not correlate with antigen specific CD8 + T-cell frequencies, which is a frequently used method for Dr. Lu-Ann Pozzi assessing CD8 + T-cell responses. These results suggest that assessing CTL functional capacity may be a superior method for evaluating CD8 T-cell response quality. The in vivo CTL assay represents a new tool for preclinical assessments of HIV vaccine candidates. Further studies are needed to determine whether CTL capacity may more reliably predict vaccine efficacy. Assessing mucosal responses with tissue explants To provide a means to investigate mucosal responses to vaccination in both NHP and humans, Dr. Carolina Herrera has developed a novel mucosal tissue explant model. In this model, mucosal tissue specimens from vaccinated NHP or humans are cultured ex vivo, and local immune responses are evaluated in culture supernatants. The explants may also be challenged ex vivo to evaluate virus neutralization capacity. In a pilot study, NHP were vaccinated with the RV144 regimen (AL- VAC and AIDSVAX B/E) and B-cell responses in cervicovaginal and colorectal tissue explant cultures, as well as in serum, were assessed. Vaccination was found to elicit Env-specific IgG and IgA antibodies both systemically and in mucosal tissues. In addition, mucosal cytokine secretion profiles were altered upon AIDSVAX Dr. Carolina Herrera boosting. The next steps will be evaluating any correlations between these vaccine-induced NHP mucosal responses to responses in humans. Human mucosal explants will be investigated in collaboration with the US Military HIV Research Program. Clinical specimens from ALVAC and AIDVAX vaccine recipients will be obtained from volunteers enrolled in the RV305 and RV306 trials in Thailand. Ex vivo viral infection of NHP and human explant cultures is planned to determine potential vaccine-induced markers of protection on mucosal surfaces. These studies will establish the utility of tissue explants to facilitate HIV vaccine development by providing a surrogate model for protective mucosal responses. Summary From assessing new approaches to recruit individuals at high risk for HIV infection to evaluating vaccineinduced responses in unprecedented detail, significant advances are being made through HVTN-supported research. These programs were established to stimulate innovative HIV vaccine research and encourage current and future researchers, both of which are critical to succeeding in our mission to enhance the discovery and drive the development of a safe and effective HIV vaccine. Acknowledgments Many thanks to Blythe Adamson, Michele Andrasik, Cecilia Morgan, and the awardees. Tracey Day is HVTN Senior Science Writer. References 1. Churchyard GJ, Morgan C, Adams E, et al. A phase IIA randomized clinical trial of a multiclade HIV-1 DNA prime followed by a multiclade rad5 HIV-1 vaccine boost in healthy adults (HVTN204). PLoS ONE. 2011;6(8):e21225. 2. Liao HX, Chen X, Munshaw S, et al. Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated. J Exp Med. 2011;208(11):2237-2249. 3. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361(23):2209-2220. 4. Russell ND, Graham BS, Keefer MC, et al. Phase 2 study of an HIV-1 canarypox vaccine (vcp1452) alone and in combination with rgp120: negative results fail to trigger a phase 3 correlates trial. J Acquir Immune Defic Syndr. 2007;44(2):203-212. 5. Haynes BF, Gilbert PB, McElrath MJ, et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med. 2012;366(14):1275-1286. 6. Kalams SA, Parker SD, Elizaga M, et al. Safety and comparative immunogenicity of an HIV-1 DNA vaccine in combination with plasmid interleukin 12 and impact of intramuscular electroporation for delivery. J Infect Dis. 2013;208(5):818-29. 16 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 17

HVTN Protocols -- Enrolling or in Follow Up TRIAL 1 PROTOCOL OPEN Oct-11 PRODUCTS DEVELOPER/COLLABORATOR DNA clade C MVA clade C gp140 with MF59 clade C inserts N Sites Description HVTN 073E / SAAVI 102 gag, RT, tat, nef, env 27 Boston; Cape Town; Soweto A phase 1 placebo-controlled study extension to HVTN 073 / SAAVI 102, to evaluate the safety and tolerability of intramuscular (IM) administration of Novartis Sub C gp140 vaccine with MF59 adjuvant, given to healthy, HIV uninfected adult participants in South Africa and the United States. Participants have previously received the SAAVI DNA vaccine followed by the SAAVI modified vaccinia Ankara (MVA) vaccine. SAAVI Novartis HVTN 076 Sep-11 DNA multiclade rad5 multiclade gag, pol, nef, env 17 Seattle A phase 1b clinical trial to evaluate mucosal immune responses to IM injections of an HIV-1 DNA plasmid vaccine prime followed by an HIV-1 recombinant adenoviral vector (rad) boost in healthy, adenovirus serotype 5 (Ad5) neutralizing antibodies (nabs) seronegative HIV-1 uninfected adults. VRC HVTN 077 Feb-09 DNA clade A rad5 clade A rad35 clade A VRC env 192 Atlanta; Birmingham; Boston; Nashville; New York; Rochester; San Francisco; Seattle A phase 1b clinical trial to evaluate the safety and immunogenicity of Ad serotype 35 (rad35) and rad5 HIV-1 vaccines, when given as a heterologous prime/boost regimen or as boosts to a recombinant DNA vaccine in healthy, Ad5-naïve and Ad5-exposed, low risk, HIV-1 uninfected adult participants. HVTN 078 Oct-09 rad5 multiclade NYVAC clade B env, gag, pol, nef 80 Lausanne A phase 1b clinical trial to evaluate the safety and immunogenicity of heterologous prime/boost vaccine regimens (NYVAC-B/rAd5 vs. rad5/nyvac-b) in healthy, HIV-1 uninfected, Ad5 nab seronegative adult participants. VRC EuroVacc HVTN 082 Jun-10 DNA multiclade rad5 multiclade env, gag, pol, nef 8 Boston; Rochester; San Francisco; Seattle A phase 1b clinical trial to examine the role of genetic background in governing immune responses following vaccination with HIV antigens delivered via a DNA prime/ rad5 boost regimen. VRC HVTN 083 Oct-10 rad5 clade A rad5 clade B rad35 clade A VRC HVTN 084 Mar-11 rad5 multiclade rad5 clade B VRC HVTN 085 Feb-12 rad5 multiclade VRC env 180 Atlanta; Birmingham; Boston; Nashville; New York; Rochester; San Francisco env, gag, pol 100 Boston; Chicago; Iquitos; Lausanne; Lima; New York; Sao Paulo gag, pol, env 90 Boston; Chicago; Iquitos; Lausanne; Lima; New York; Sao Paulo A phase 1 clinical trial to assess the safety, tolerability, and ability to increase breadth and magnitude of immune responses of prime/boost vaccine regimens in healthy, HIV-1 uninfected adults, by using different combinations of heterologous inserts (env from different HIV-1 clades) and heterologous vectors (recombinant adenovirus vectors of different serotypes). A randomized, double blind, phase 1b trial designed to examine the influence of antigenic competition on the immunogenicity of HIV-1 Gag-Pol. The goal of this study is to determine whether the breadth and magnitude of T-cell responses to Gag and/or Pol is altered by co-immunization with Env. A phase 1b randomized double-blind clinical trial to examine whether polytopic administration of VRC rad5 gag-pol, env A/B/C vaccine enhances HIV-specific cellular immune responses in humans. HVTN 086 Dec-11 DNA clade C MVA clade C gp140 with MF59 clade C SAAVI Novartis HVTN 087 May-12 DNA clade B rvsv IN clade B 1 As of August 2013 Profectus gag, RT, tat, nef, env gag, pol, nef, tat, vif, env, IL-12 184 Cape Town; Klerksdorp; Soweto A phase 1 placebo-controlled clinical trial to evaluate the safety and immunogenicity of SAAVI DNA-C2, SAAVI MVA-C and Novartis subtype C gp140 with MF59 adjuvant in various vaccination schedules, in HIV uninfected, healthy, vaccinia-naïve adult participants in South Africa. 100 Nashville; New York; Philadelphia; Rochester A phase 1 trial to evaluate the safety and tolerability of a prime/boost regimen of HIV-1 multiantigen vaccine given with and without plasmid human IL-12, delivered with electroporation, followed by a recombinant vesicular stomatitis virus serotype Indiana (rvsv IN )N4CT1gag1 boost in healthy, HIV uninfected adult volunteers. GM-CSF = granulocyte-macrophage colony-stimulating factor; IL-12 = interleukin 12; MVA = modified vaccinia Ankara; NYVAC = New York Vaccinia; rad5 = recombinant adenovirus serotype 5; rad35 = recombinant adenovirus serotype 35; rvsv = recombinant vesicular stomatitis virus. 18 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 19

HVTN Protocols -- Enrolling or in Follow Up TRIAL 1 PROTOCOL OPEN PRODUCTS DEVELOPER/COLLABORATOR HVTN 088 Jul-11 gp140 with MF59 clade C Novartis HVTN 090 Oct-11 rvsv IN clade B Profectus HVTN 092 Apr-13 DNA clade C NYVAC clade C EuroVacc IPPOX BMGF HVTN 094 May-12 DNA clade B MVA clade B GeoVax HVTN 096 Aug-12 AIDSVAX B/E (Subtypes B, E gp120) with alum DNA clade C NYVAC clade C IPPOX EuroVacc GSID USMHRP HVTN 097 Apr-13 ALVAC-HIV multiclade AIDSVAX B/E (Subtypes B, E gp120) with alum Tetavax ENGERIX-B inserts N Sites Description N/A 40 Birmingham; Nashville; Seattle The primary objectives of this phase 1 open-label trial are: 1) To evaluate the safety and tolerability of HIV-1 Sub C gp140 vaccine with MF59, and 2) To evaluate neutralizing antibody responses to HIV-1 Sub C gp140 vaccine with MF59, in healthy, HIV-1 uninfected adults, primed or unprimed with HIV-1 subtype B envelope subunit vaccines with MF59. gag 60 Atlanta; Nashville; Philadelphia; San Francisco A phase 1 placebo-controlled clinical trial to evaluate the safety and immunogenicity of rvsv IN HIV vaccine given to healthy, HIV-1 uninfected adult participants. The primary objective of this dose-escalation trial is to establish the maximum safe and tolerated dose of a rvsv IN HIV gag vaccine being given for the first time in humans. gag, env, pol, nef 209 Atlanta; Birmingham; Boston; Chicago; Lausanne; Philadelphia; San Francisco; Seattle GM-CSF, PR, RT, gag, env, tat, rev, vpu A phase 1 clinical trial to evaluate safety and compare the immunogenicity of 3 DNA vaccine prime schedules followed by a NYVAC vaccine boost in healthy, HIV- 1 uninfected adult participants. The primary objectives are to: 1) evaluate the safety and tolerability of DNA alone and DNA prime followed by NYVAC boost in HIV uninfected healthy adults; and 2) compare the effect of each of 2 different accelerated priming schedules to the historical schedule on T-cell responses following the NYVAC boost. 48 Birmingham; Boston; Rochester; San Francisco The primary objective of this trial is to evaluate the safety and immunogenicity of a heterologous prime/boost vaccine regimen of GEO-D03 DNA and MVA/HIV62B vaccines in healthy, HIV-1 uninfected vaccinia naïve adult participants. pol, nef, gag, env 96 Lausanne A phase 1 double blind placebo-controlled clinical trial to evaluate the safety and compare the priming ability of NYVAC alone versus NYVAC + AIDSVAX B/E, and DNA alone versus DNA + AIDSVAX B/E when followed by NYVAC + AIDSVAX B/E boosts in healthy, HIV-1 uninfected adult participants. env, gag, PR 100 Cape Town; Klerksdorp; Soweto This 1b randomized double blind placebo controlled clinical trial evaluates the safety and immunogenicity of the vaccine regimen ALVAC-HIV (vcp1521) followed by AIDSVAX B/E in healthy, HIV-1 uninfected adult participants in South Africa. The study further attempts to elucidate immune responses to the HIV vaccine regimen, by comparing them to immune responses elicited by licensed tetanus or hepatitis B vaccines. Sanofi Pasteur GSID USMHRP GSK HVTN 205 Feb-09 DNA clade B MVA clade B env, pol, gag, tat, rev, vpu, PR, RT 299 Atlanta; Birmingham; Boston; Iquitos; Lima; Nashville; New York; Rochester; San Francisco; Seattle A phase 2a clinical trial to evaluate the safety and tolerability of a prime/boost regimen of a DNA vaccine and an MVA vaccine, or MVA vaccine alone, in healthy, HIV-1 uninfected, vaccinia-naïve individuals. GeoVax HVTN 503-S May-13 No Products N/A TBD Cape Town; ethekwini; Klerksdorp; Medunsa; Soweto The primary objectives of this sub-study are to expand HIV diagnostic testing coverage and information on behavioral risk, among the HVTN 503 (Phambili) study cohort. HVTN 505 Jun-09 DNA multiclade rad5 multiclade env, nef, pol, gag 2504 All US Sites A phase 2b, randomized, placebo-controlled, test-of-concept trial to evaluate the effect of the VRC DNA/rAd5 vaccine regimen on the rate of HIV-1 acquisition, and on HIV-1 viral load setpoint, compared to placebo participants who are diagnosed with HIV-1 infection at or after Day 196 post-enrollment through Month 24 visit. VRC HVTN 910 Dec-11 No product N/A N/A Atlanta; Birmingham; Boston; Cape Town; Chicago; Iquitos; Klerksdorp; Lausanne; Lima; Nashville; New York; Philadelphia; Port au Prince; Rochester; San Francisco; Sao Paulo; Seattle; Soweto This protocol assesses the persistence of HIV vaccine-induced seropositivity in participants who received study vaccines in -funded preventive HIV vaccine trials. The primary purpose is to describe how long vaccine-induced antibodies to HIV, detectable on commercially available HIV antibody test kits, persist. 1 As of August 2013 GM-CSF = granulocyte-macrophage colony-stimulating factor; IL-12 = interleukin 12; MVA = modified vaccinia Ankara; NYVAC = New York Vaccinia; rad5 = recombinant adenovirus serotype 5; rad35 = recombinant adenovirus serotype 35; rvsv = recombinant vesicular stomatitis virus. 20 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 21

HVTN Efficacy Trials Results HVTN Efficacy Trials Results Adi Ferrara Earlier this year, data for 2 HVTN efficacy studies -- HVTN 503 (final efficacy analysis) and HVTN 505 (results from an interim data safety and monitoring board [DSMB] unblinded review) --were released. Both analyses were planned the HVTN 503 final efficacy analysis occurred at the end of 3.5 years of followup of the participants. The HVTN 505 interim unblinded analysis of efficacy was triggered, as specified in the protocol, when the 30th Week 28+ infected individual had 20 weeks of follow-up post-diagnosis. Both analyses offer important lessons and raise interesting questions in the challenging HIV vaccine trials field. Phambili (HVTN 503) Final Efficacy Analysis HVTN 503 (also known as Phambili) was a trial carried out in South Africa (a clade C region) using the same Merck recombinant adenovirus serotype 5 (rad5) HIV-1 clade B (gag, pol, nef) vaccine used in the Step Study. The regimen consisted of 3 injections of the vaccine at weeks 0, 4, and 26. When the Step Study vaccinations were halted due to non-efficacy (September, 2007), vaccinations in Phambili were also stopped. At that time, 801 people were enrolled in Phambili (out of a planned enrollment of 3,000); of the 400 people in the vaccine arm 29 people had received all 3 injections, 259 people had received 2 injections, and 112 people had received only the first injection. All 801 participants were unblinded when vaccinations were halted. In the Step Study, the final data analysis showed that vaccine recipients were at increased risk of HIV acquisition, compared with placebo recipients. 1 The initial analysis of HVTN 503 revealed 14 HIV infections, 8 in vaccine recipients and 6 in the placebo group. Once unblinded, follow-up of participants continued for 3.5 years; 189 participants were lost to follow-up during that period. The results of the final efficacy analysis, summarizing this longer follow-up period, were reviewed in March 2013. The results showed that of 100 participants who became infected and completed follow-up, 63 were vaccine recipients, and 37 received placebo. The higher rate of acquisition in the vaccine arm became pronounced around 30 months following first vaccination, and was greater in men. No baseline risk factors, including circumcision status or presence of Ad5 neutralizing antibodies, seemed correlated with this increased acquisition rate. However, as the total number of participants in HVTN 503 was small due to early termination of vaccinations, the study may have been underpowered to detect a small effect of a specific risk factor on the risk of HIV acquisition, if such an effect existed. These results raise several questions. It is unclear at this point what caused the increased number of infections in the vaccine arm, compared to placebo. If this is a late biological effect of the vaccine, it is highly unusual for one to appear so late in the follow-up period when vaccine affects should actually wane, according to Dr. Glenda Gray, the study Chair. There are also several nonbiological possibilities that investigators have raised, including: 1. The early unblinding of the study may have biased the results. (For example, risk behavior may have been affected by the unblinding.) 2. People from both study arms were lost to followup (88 from the vaccine arm, 101 from the placebo arm), and their infection status is unknown at this point. If more dropouts in one arm got infected compared to another, the actual results might be different than what is reflected in the final analysis. In an effort to clarify the results of the final efficacy analysis, the HVTN is implementing a follow-up protocol, 503-S. The new protocol will invite Phambili participants back to their clinical sites for blood tests (including HIV tests), behavioral assessments, and further risk reduction counseling. Investigators are very interested in finding the missing 189 participants that were lost to follow-up, and verifying their HIV status. HVTN 505 DSMB Report HVTN 505 was a phase 2b proof-of-concept study testing a prime-boost vaccine regimen consisting of a DNA prime and a rad5 boost. Both vaccines were developed by the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center (VRC). The study was designed to evaluate the vaccine s ability to prevent HIV infection, and if the vaccine reduced viral load in vaccinees that later became infected with HIV. Enrolled participants were men and transgender individuals who have sex with men. Participants were offered extensive risk reduction counseling, as per standard HVTN protocol. The prime-boost regimen under study comprised a series of four immunizations, beginning with a DNA prime (clade B gag, pol, nef and clades A/B/C env) given at months 0, 1, and 2. This priming series was followed by a single injection at month 6 of a rad5 boost (clade B gag-pol and clades A/B/C env). The study enrolled 2,504 volunteers at 21 sites in 19 US cities. As an added precaution due to the Step Study results, 2 participants had to be circumcised and free of neutralizing antibodies to Ad5 at enrollment; HIV infections were reviewed by an independent statistician as they occurred, to ensure that there were not significantly more infections in the vaccine arm, compared with the placebo arm. On April 22, 2013, an independent DSMB found that the vaccine regimen did not prevent HIV infections, nor did it reduce viral load in infected participants. The DSMB recommended halting further vaccinations, and vaccinations were discontinued as of April 23, 2013. The DSMB based its recommendation on information gathered from 2,494 volunteers (1,250 volunteers in the study vaccine arm, and 1,244 volunteers in the placebo arm). The primary analysis looked at volunteers diagnosed with HIV infection after having been in the study a minimum of 28 weeks. This was done to allow enough time for the vaccine regimen to be given and stimulate an immune response. This analysis found that 27 HIV infections occurred among the vaccine recipients, and 21 infections occurred among the placebo recipients. The DSMB also looked at data for volunteers who became HIV-infected during the first 28 weeks of the study; there were 14 cases among participants who received the study vaccine regimen, and 9 infections among the placebo recipients. Thus, the overall number of HIV infections in the study, occurring between enrollment and the month 24 study visit, came to 41 in study vaccine recipients and 30 among the placebo recipients at the time of the DSMB s review. The increased number of cases in the study vaccine arm, compared to the placebo arm, is not statistically significant. It is not clear why this difference exists. Further analysis is needed in order to draw any firm conclusions. Study investigators will continue following all study participants for five years from the time of enrollment. Discussion It is important to keep in mind that analyses of both HVTN 503 and 505 bring into focus not only the realities of conducting clinical research, where unexpected or disappointing results occur with some frequency, but also the strengths of the HVTN s study designs and commitment to its study participants. HVTN 505 did exactly what it was designed to do: it provided a swift, decisive answer to the questions posed by the investigators is this vaccine regimen efficacious as prevention? Is it efficacious after exposure, in lowering the viral load of participants who become infected? When the answers came to light, as disappointing as they were, the Network responded speedily, halting all further vaccinations within 24 hours and notifying participants of the results immediately. The results of HVTN 503 s final efficacy analysis were likewise met with speedy action. Local regulatory authorities in South Africa were apprised of the results by the protocol leadership and the notified the US FDA. A new follow-up protocol was written in a matter of weeks, aiming not only to help answer the puzzling questions arising from the new data, but also in the interest of the original study s participants. The HIV vaccine field is complex and ever-changing, and the HVTN is pursuing several promising vaccine strategies, with different products and combinations, Continued on page 34 22 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 23

signs of the time: Technology Updates at the HVTN The HVTN and SCHARP have embarked on several projects to update the technology used in their daily operations. 2 4 2a. main PROTOCOL landing page signs of the time: technology updates at the hvtn 1 HVTN Members Site Moves to a SharePoint Platform Alicia Yamamoto Launched on August 19, the HVTN s newly designed members site (https://members.hvtn.org) is now available to the Network. The main reason for updating the site was compliance driven. Since the old HTML-based site was not up to current standards for user and site security, moving the site to a new platform (SharePoint) was an efficient way to bring it up to date, while making it easier for HVTN staff to update content on their own. Moreover, SharePoint affords other advantages, such as more efficient workflow and document versioning, making the decision to move to this platform easier. Since the existing site was approximately 10 years old, other considerations for the site s redesign included: improving the users experience (the look and feel of the site, including improved navigation), refreshing the site s content, reducing the need for web developer resources, and using role- and section-level permissions for all users, including some groups that did not previously have access to the HTML-based members site (eg, expansion sites). Improved User Experience and Fresh Content In addition to eliminating outdated headings and content, the new members site includes a new clinical research site area, Site Support, (Figure 1, #1) with content organized functionally. Key new features in this area include menu items with information about the HVTN s Community Engagement program, and a new VISP Resources page. On the Community Engagement page, users will find a directory of educators and recruiters, including contact information, photo, and role. This page also features a table of community members representation on protocol teams. Figure 1. Landing page of the new HVTN Members Site. 1 members' HOME PAGE 5 Enhanced search features include the ability to search by specific section (eg, search for a document in a specific page or section instead of across the whole site). The site features several additional new areas and reorganized content, some of which are discussed below. In order to better organize protocol-specific content, the new site has moved away from one long page containing all documents per protocol to a landing page with key document-type headings (Figure 2a, #2). The new site design uses familiar file headings to organize information. For example, if a user clicks on Study Materials or Protocol Documents and Communications that section will open on a new page (Figure 2b, #3). Other enhancements to the protocol landing page include links to key cross-protocol resources (reports, 6 3 Figure 2. Protocol landing page and subpages. 2a. Main protocol landing page. 2b. After clicking on Protocol Documents and Communications, this is the new page that opens. 2b. PROTOCOL SUBpage the HVTN Manual of Operations (MOP), etc.; Figure 2a, #4), and new fields for conference call minutes (Figure 2a, #5) and events (Figure 2a, #6). Evaluation Under Site Support on the Evaluation page, personnel have access to the Network Evaluation Committee (NEC) reports for their clinical research site, as well as overall Network evaluation reports, NEC standards and indicators, and 24 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 25

signs of the time: technology updates at the hvtn signs of the time: technology updates at the hvtn other performance-related resources. This location increases transparency of the evaluation process and observations and provides an easily accessible central repository for the NEC reports and supporting materials. HVTN Scholars and Initiatives Programs The Training tab now includes a new landing page for the various HVTN scholars and initiative programs, with links to profiles of scholars. The new page features the Research and Mentorship Program (RAMP) for Black and Latino/Latina medical students (with links to resources for current scholars and alumni), the South African/ HVTN AIDS Vaccine Early Stage Investigator Programme (SHAPe), the HVTN/CHAVI Non- Human Primate (NHP) Early Stage Investigator (ESI) Scholar Program, and the HVTN Initiatives Program (HIP). When application periods open for any of these programs, an announcement will also be posted on this page. reducing the need for web developer resources Leveraging the flexibility and usability of a Share- Point platform, the new HVTN Members Site enables groups within the HVTN to manage their own content. Instead of centralized ownership where groups rely on a web developer for posting content, each group will be responsible for handling its own updates. This change should increase efficiency, reduce bottlenecks, and help ensure that members have access to the most up-to-date information. new permissions structure and expanded access Improved security was the primary driver for the redesign. The HVTN created individual user accounts with role-based access and page-level permissions, to replace group logons and shared passwords. This improvement allows for finer control over website access, as Network staff change over time. Not only is this new access control more efficient from a user standpoint, since users will only see the navigation items to which they have access, it also minimizes the need to post and maintain content in multiple places with various access restrictions. The new, more robust account permission options mean that other groups that didn t previously have access to the Members Site, such as expansion sites members, will now have this access. These users no longer have to go to a separate area to access most study-related materials and protocol-related documents. (Data-related materials and tools remain on Atlas.) In addition, current and future expansion site personnel will now be able access tools and resources that were previously unavailable to expansion site members on the old site. These include the HVTN Directory, Manual of Operations (MOP), and training resources. accessing the members' site To establish access to the new Members Site, new users joining the HVTN must complete an account request form. The HVTN account manager will create an account for them and assign permissions to this account, consulting any approvers as needed. The account will be created within 24 hours of approval and the new user will be notified. This process should be completed within 2 business days. New users will also be able to access training materials through a link in the Welcome Email and on the support page at https://members. hvtn.org/support/sitepages/tutorial.aspx. redesign of hvtn site on atlas Sara Shoemaker As the Statistical Data Management Center for the HVTN, the Statistical Center for HIV/AIDS Research and Prevention (SCHARP) manages data of many different types and from different sources. One way the Network accesses that data is via the Atlas web portal. It serves a broad range of user groups within the HVTN by hosting not only data but also reports and documents, as well as tools for uploading and interacting with the data. The amount of content posted on the HVTN s Atlas site has slowly grown since its inception, and had reached a point where a major reorganization and re-visioning of the site was required for it to remain effective. SCHARP Information Systems, in partnership with LabKey Software (the developer of the platform used by Atlas) recently 1 Menu bar allows easy access to your major folders 2 New area for Safety teams 3 Dashboards list all Protocols and Sites and let you jump to those you have permission to see 4 Use column filters to list sites for a given Protocol 5 Shortcuts provide easy access to commonly used tools 1 3 3 Figure 3. The HVTN home page on Atlas, with dashboards and shortcuts. 4 completed a project to update the site. During the redesign process we sought input from various users and performed usability testing, incorporating the results into the final design. The redesign project goals included the following: 1) to improve the look and feel of the site, 2) to refine the site s navigation, 3) to enhance the Network activities visibility on Atlas, and 4) to reduce the cost of operating the site by streamlining posting of data and documents by support staff. The redesign was rolled out in 2 stages: the 1st stage deployed in the spring, and the 2nd in early August. A summary of the main changes incorporated in the portal with the redesign is presented below. 2 5 ATLAS HOME PAGE 26 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 27

signs of the time: technology updates at the hvtn signs of the time: technology updates at the hvtn TITLE Main Areas of Feature Improvement The HVTN Home Page One prominent change is the addition of dashboards, now located on the HVTN home page (Figure 3). A list of all HVTN protocols along with their short titles is shown and can be used to navigate to a protocol s folder on Atlas. A list of sites and their associated protocols is also presented, along with the new Shortcuts panel that allows the user to jump to frequently-used tools. Project Navigation Another main improvement is the introduction of new ways to allow the users to navigate to their content and tools: the new red menu bar under the header being a noticeable addition (Figure 4). The content on the site has been reorganized into categories that are each represented by a menu in the menu bar. Also new in the release of LabKey 13.2 in August, the side menu is retired and the users can access Atlas s folder tree as a drop-down menu. This has the advantage of increasing the amount of content that can appear on a page. Along with the new drop-down menu, the server now presents a navigation trail ( breadcrumb ) that allows easy traversing to a page s parent folder with a single click. Folders for Protocols, Sites and Labs One of the major goals of the redesign was to provide better access to commonly used items. To accomplish that, the site builds on the concept of a main folder for each protocol, site and endpoint lab that was already in use on Atlas (Figure 5). These folders now make use of navigation tabs (found in the upper right of the page) accessing pages that host content important to the folder s user. The main folders also provide a workspace and links directing users to other commonly used pages or sites. Investigator Data Browsing A recent initiative within the HVTN is to make study data more readily available to investigators within the Network. To achieve this goal, SCHARP has begun posting CRF data from closed studies on the Atlas website. A new Investigator Data table is available under the Data menu, providing users a quick, filterable summary of the different elements of HVTN studies and links to the posted data. The Document Manager For Atlas support staff, a lot of time is taken up in the posting and management of content. A new document management tool was developed, providing easy upload of protocol documents and PTID lists. After being uploaded, the document automatically becomes listed and available for download in the appropriate Site or Protocol folder. The tool also handles document versioning and archiving of documents no longer needed. In the future, this feature can be extended to handle additional types of documents. The redesign of the HVTN site on Atlas, produced by SCHARP Information Systems working with LabKey Software, was completed this summer with the deployment of the new navigation menu. The team thanks all the users that participated in the user testing and supplied us with feedback during the launch this spring. 1 Click on Project icon to launch Project Menu 2 Folder Menu allows access to all folders in the HVTN project 3 Use the Navigation Trail to browse to parent folders 4 Use '+' icon to expand as in former left navigation menu 1 Reports and Protocol Documents are available on front page 2 Shortcuts for easy access to tools 3 Tabs for commonly used items 4 Links to other relevant areas 1 2 4 Figure 4. Atlas navigation with the new project and folder menus. 3 1 3 3 2 2 ATLAS projects 4 Figure 5. Home pages for protocols, sites, and labs. atlas protocols, sites, labs 28 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 29

signs of the time: technology updates at the hvtn signs of the time: technology updates at the hvtn real-time error detection and more with electronic data capture Drienna Holman I know what you re thinking. You can manage your bank account online, so why can t you enter your study data online, right? Well, now you can, with idatafax electronic data capture! What is idatafax Electronic Data Capture? idatafax is a software program that allows sites to enter case report form (CRF) data directly into SCHARP s clinical data management system (CDMS) via electronic data capture, or EDC. Why EDC? Beyond the convenience of being able to complete forms electronically, probably the biggest benefit of using EDC is the increased efficiency in the data QC process, reducing the time and effort needed to obtain clean study data. Real-time checks alert users to potential errors that can be fixed during data entry (eg, vital signs out of range, missed entries), and sites will no longer have to wait for bi-monthly reports to fix data entry problems (QCs) they ll be able to view and correct them on a schedule that works best for them. SCHARP has been keeping an eye on evolving EDC technologies for several years. Many HVTN sites have experience using EDC through research projects outside the HVTN and have requested EDC for HVTN studies. Last year, SCHARP began to actively search for a CDMS with EDC capability to supplement or replace SCHARP s current system, DataFax. We started with an assessment of EDC systems that were appropriate for the conduct of clinical trials and would support a global network with varying degrees of technical infrastructure. Viable candidate systems needed to be robust, facilitate compliance with required data standards, be reasonably priced, and not require a massive effort to implement. Another important feature was the ability to implement the system in a way that wouldn t disrupt ongoing studies already using DataFax. It was about this time that Clinical DataFax Systems, Inc., the makers of DataFax, released the new idatafax version. Compared to the other software packages assessed, idatafax not only met all the critical requirements we were looking for in a CDMS system with EDC, but it also had some distinct advantages over other systems. This new web-based version is a hybrid system that allows for data submission via EDC or the traditional image-based (fax) method. It also had the added benefit of being a robust system familiar to and trusted within SCHARP, where the infrastructure and expertise needed to operate the system already exists. The decision was made to implement an EDC pilot in HVTN studies, using idatafax, by the end of 2013. To EDC or not to EDC? One of the more attractive aspects of this hybrid idatafax system is that it gives sites the flexibility to choose the method of transmission that works best for them. For each study where EDC is available, sites can choose to enter data by EDC or continue to fax all CRFs for processing by SCHARP. Sites that choose to enter data by EDC will use EDC to submit any CRF that cannot be used as a source document (eg, local labs and administrative forms). For the remaining CRFs, sites will have the option to submit data by EDC or fax. Even if sites decide not to use EDC, all sites will be able to view their QCs in idatafax. The Rollout Fax, installing the software at six sites and giving them view access to their QCs. We then created a test study and conducted usability testing at the HVTN Full Group Meeting in May, to get feedback on the interface. The usability test simulated data entry for a mock HVTN study using a set of scenarios. The test study and usability testing proved highly informative, and those lessons are put into action in HVTN 092. The SCHARP team is retrofitting HVTN 092 by modifying the study setup, database, and related systems (eg, safety monitoring and reporting, AE coding, and quality checks To protect the study data, SCHARP is taking a phased approach to rolling out EDC, making sure that we identify and resolve a contained set of issues before moving to the next phase. Over the last several months, SCHARP conducted a pilot study to get initial user experience with idatataking the mystery out of cdisc Drienna Holman You may have heard someone talking about it in a breakout session at the last HVTN Full Group Meeting. Or maybe you remember seeing something about it in a grant application...what was it called again...cdisc? CDISC sounds like it could be one of those popular TV dramas, involving an international organization working with major corporations on a mysterious mission that no one seems to understand. But what s CDISC really about? What is CDISC? CDISC, or the Clinical Data Interchange Standards Consortium, is an international organization, and yes, it does have a lot of big names involved. CDISC members and sponsors are volunteers who come from pharmaceutical companies, clinical research organizations, and academic institutions. They are joined together in a common mission -- to develop and support harmonized standards for collection, exchange, submission, and archival of that run at night). The process is expected to be similar to that for implementation and setup of a new study, with the addition of the new EDCrelated setup activities and modifications to related systems adjusted to accommodate EDC. When Will It Be Ready? Following the experience with HVTN 092, SCHARP plans to implement EDC for new studies that open in 2014. Stay tuned for the launch of idatafax EDC - coming soon! We ll let you know when you can get your hands on it! data from clinical studies. Sounds intriguing, right? CDISC standards are designed with maximum accessibility in mind. To encourage organizations to adopt them, the standards are vendor-neutral, platform-independent, and freely available (on cdisc.org). CDISC has been developing a comprehensive set of models -- a collection of concepts and rules used to structure and define data. (Models also serve to provide valuable context to aid in communication about the data between organizations.) Models have been developed to cover each stage in the lifecycle of a study, starting with the protocol, and going through data collection, data tabulation (for submission to regulatory authorities), analysis, and data exchange. Figure 6 shows an overview of the CDISC models for data standards at each study stage. The CDISC Models CDISC models (known by their acronyms, eg, CDASH, SDTM, ADaM) focus on different study stages and uses of the data. The most important CDISC model for SCHARP and our sponsors is the SDTM -- Standard Data Tabulation 30 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 31

signs of the time: technology updates at the hvtn signs of the time: technology updates at the hvtn Figure 6. Overview of CDISC models for data standards, by study stage. Red frames indicate CDISC models SCHARP intends to be compliant with by December 2014. CDASH = Clinical Data Acquisition Standards Harmonization; SDTM = Standard Data Tabulation Model; ADaM = Analysis Data Model. Figure 7. Summary of conversion of study data to SDTM format. The bottom table shows the source data that comes from the CRF into SCHARP s study database. The top two tables show how the data elements from the study database and metadata from a local lab reference range database (lab normals) are mapped onto the SDTM tables. Model. SDTM is used for regulatory submission. This model defines a standard structure where the data is put into tables organized within a set of categories (interventions, events, and findings). These tables are designed to maximize compatibility with common software tools used by regulatory authorities, such as the FDA, for reviewing the data. The Clinical Data Acquisition Standards Harmonization (CDASH) model standardizes the way data is collected to facilitate the generation of SDTM tables. You can think of CDASH as building in the conventions for SDTM further upstream, during data collection, to make the creation of the SDTM tables more efficient. The Analysis Data Model (ADaM) is a set of guidelines and examples for analysis datasets used to generate statistical results for submission to FDA. ADaM specifies a standard for the data structure and associated metadata for analysis datasets, and defines the fundamental principles that apply to all analysis datasets. Why Adopt CDISC at SCHARP? Having managed the data for over 175 studies, SCHARP has developed its own set of standards for use across the NIAID networks (HVTN, HPTN, MTN, and IMPAACT) studies. Ultimately, adopting a more broadly accepted model, utilized by a larger community, is beneficial not only to SCHARP, but also to the networks and sponsors we support. One of the main goals of getting organizations to adopt data standards is to facilitate cross-study comparisons by establishing and applying global standards for data elements and structures. As statistical and data management center, we also hope it will help make database development during set up of a new study more efficient. CDISC has been one of a number of models for data standards which have gained recognition over the last several years. However, more recently, the FDA has indicated a preference for the CDISC model. Although not yet an official requirement, the FDA is currently requesting that data submissions be compliant with CDISC standards. How is Data Converted to SDTM? When a sponsor plans to submit a study to a regulatory authority, like the FDA, SCHARP converts the final study data into the SDTM format, mapping data elements to specified SDTM variables and reorganizing the data into specified categories, referred to as observation classes and domains. We re essentially telling the story about that study, by providing details in a predefined way. To begin the conversion to SDTM tables, the SCHARP conversion team goes through all the study data and determines the appropriate categories (observation classes and domains) for the data. Next, the required SDTM variables for those domains are identified and mapped to the study data from the original datasets (case report forms, assay data from the labs, and questionnaire data from online survey tools) and to additional study-related metadata from other sources (eg, normal ranges for lab values). Figure 7 shows an example of how the study data and metadata for local safety lab data are mapped onto the SDTM variables. Once the mapping specifications are defined, automated mapping programs are generated that use those specifications to convert the original data sets into the SDTM data tables in SAS format. A final document, called a Define File, is generated in XML (with hyperlinks) to summarize which domains are included and to show how the data was mapped. SCHARP s CDISC Plan To be CDISC compliant means to follow the rules and conventions defined by the CDISC models. Because there are different CDISC models (eg, CDASH, SDTM, ADaM) that focus on different aspects of the data, it s possible to be compliant for one CDISC model, but not follow all the models. SCHARP s goal is to be SDTM and CDASH compliant for new studies opening December 2014 or later, after which data to be analyzed or submitted to the FDA could be requested in SDTM format at any point during or following 32 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 33

the trial. In the meantime, the plan is to have processes in place by the end of this year, should a sponsor request an unplanned SDTM conversion for an existing study. At the request of the MTN, SCHARP is taking the first step toward these goals by piloting the conversion process on an existing MTN study and creating mapping specifications for all our standard forms. This conversion exercise will provide valuable experience that will be applied to the HVTN and other NIAID networks. A new version of DataFax (the data capture / management system used by SCHARP) is expected this year that will provide additional support for SDTM and CDASH standards. As SCHARP gains more experience with CDISC and the process for converting studies to SDTM, we are reminded that each study has its own interesting story to tell and most of them are mysteries. Who knows, maybe they ll make a miniseries about them! Alicia Yamamoto is HVTN Project Manager; Sara Shoemaker is SCHARP Information Systems Technical Project Manager; Drienna Holman is SCHARP Program Manager - Special Projects. Resources at a Glance: Members Site To request an account: vtn.core.webaccounts@hvtn.org For questions about the new Members Site: Consult the support page at https://members. hvtn.org/support Contact membersupport@hvtn.org HVTN Portal on Atlas Questions, issues, and comments: atlas@scharp.org. idatafax: http://www.datafax.com/software/idatafax/ HVTN Efficacy Trials Results, continued from page 23 including planned efficacy studies in southern Africa. While we know that not all vaccine strategies will prove successful, the Network, sites staff, and most importantly our dedicated trial volunteers all recognize that finding a safe, globally effective HIV vaccine is crucial to ending the HIV/AIDS pandemic. Those of us involved in the search for an HIV vaccine may not always be happy with the answers we get in our studies, but we keep searching for the right one. Acknowledgments The author would like to thank Libby Adams, Mary Allen, Chuka Anude, Glenda Gray, Scott Hammer, and Shelly Karuna for their review and invaluable feedback on this article. Adi Ferrara is HVTN Technical Editor / Writer. References 1. Duerr A, Huang Y, Buchbinder S, et al. Extended follow-up confirms early vaccine-enhanced risk of hiv acquisition and demonstrates waning effect over time among participants in a randomized trial of recombinant adenovirus hiv vaccine (Step Study). J Infect Dis. 2012;206(2):258-266. 2. Buchbinder SP, Mehrotra DV, Duerr A, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet. 2008;372(9653):1881-1893. Additionally, the data presented here were disclosed in official NIAID communications, and accurate as of their publication dates: HVTN 503: Regulatory Officials Informed of HVTN 503 HIV Vaccine Trial Findings -- http://www.niaid.nih.gov/news/newsreleases/2013/ Pages/phambili.aspx HVTN 505: NIH Discontinues Immunizations in HIV Vaccine Study -- http://www.niaid.nih.gov/news/newsreleases/2013/pages/ HVTN505April2013.aspx The HIV Vaccine Trials Network at AIDS VACCINE 2013 Satellite Session: Thursday, October 10, 2013, 15h00-17h00, Room 124 + 125 Meta-Analysis of HVTN Efficacy Studies with Adenovirus Vectors The HVTN has conducted a series of efficacy trials involving recombinant adenovirus type 5 (Ad5)-containing vaccines. Despite high rates of immunogenicity, none of the trials found a reduction in the primary or secondary endpoints of reducing HIV acquisition or post-acquisition viral load. This session will present overviews and updates on the individual trials and a meta-analysis of the three trials, to prompt discussion regarding the findings and future directions of adenovirus-based vaccines for HIV and other diseases. AGENDA: Introduction Larry Corey Immunogenicity of Ad5 Based Vaccines Julie McElrath and Georgia Tomaras Overview and Update of the Step Study (HVTN 502) Susan Buchbinder Overview and Update of Phambili (HVTN 503) Glenda Gray Overview and Update of HVTN 505 Scott Hammer Meta-Analysis of HVTN Experience with Adenovirus Vectors Peter Gilbert Invited Guests Presenting HVTN Data: Opening Session: Magda Sobieszczyk Plenary 4, Emerging Clinical Trial Data: Georgia Tomaras and Glenda Gray Roundtable Discussion, Clinical Trial Follow-up and Retention: Glenda Gray, Scott Hammer, and Susan Buchbinder Symposium 1, Innate Immunity: Dan Zak Symposium 4, Viral Vaccine Vectors: Harriet Robinson 34 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 35

The HIV Vaccine Trials Network at AIDS VACCINE 2013 The HIV Vaccine Trials Network at AIDS VACCINE 2013 Oral abstract Presentations: Hancock G, Yang H, McMichael AJ, et al. Effective antiviral CD8 + T cells responses are rare in HIV-positive Step & Phambili study participants but are targeted to low entropy viral epitopes. Williams WB, Jones K, Liu P, et al. Antibody repertoire induced by the multiclade (Env A,B,C) HIV-1 DNA prime, rad5 boost VRC vaccine. Poster Discussion Presentations: Deschamps MM, Zorrilla C, Morgan C, et al. Feasibility of enrolling female commercial sex workers at high risk of HIV infection for HIV vaccine trials in the Caribbean. Frank I, Grunenberg N, Hural J, et al. Enhanced HIV-specific CD8 + T cell responses following polytopic administration of VRC rad5 gag-pol/env A/B/C in HIV-uninfected healthy adults. Huang Y, Duerr A, Moodie Z, et al. Immune-correlates analysis of the Step HIV vaccine efficacy trial a post-hoc analysis of HIV-specific and non-specific cellular immune responses. Poster Presentations: Adamson B, Fuchs J, Johnson P, et al. Development of an early stage investigator scholar program for preclinical researchers. Adamson B, Hertz T, Duerr A, et al. Baseline predictors of immunogenicity in HVTN 204. Adamson B, Wakefield S, Flood D, et al. HVTN mentored research program for black and Latino/a medical students increases intent to pursue a career in HIV/ AIDS vaccine research. Cerwensky K, Laher F, Otwombe K, et al. Predictors of HVTN 503 MRK AD5 HIV- 1 gag/pol/nef vaccine-induced immune response. Coombs A, McFarland W, Ick TO, et al. Long-chain peer referral to recruit black MSM and black transgender women for an HIV vaccine efficacy trial. De Rosa SC, Frahm N, Diaz G, et al. No increase in activated T cells and limited increase in adenovirus-specific T cells in colon and rectal mucosa following HIV-1 DNA/rAd5 immunization. Poster Presentations (cont.): Deschamps MM, Joseph P, Severe K, et al. Strategy to conduct vaccine trials: The GHESKIO experience. Ducar C, Smith D, Stirewalt M, et al. Benefits of a comprehensive, semi-automated quality program for cryopreserved PBMC covering 29 globally distributed clinical trials sites. Flood D, Wallace M, Racow K, et al. Attracting, equipping and retaining young investigators in HIV vaccine research in South Africa. Fuchs JD, Frank I, Kochar N, et al. A recombinant vesicular stomatitis virus (rvsv) HIV-1 gag vaccine is safe and immunogenic in healthy, HIV-1 uninfected phase I trial participants. Hammer S, Sobieszczk M, Janes H, et al. HVTN 505: Efficacy of a multi-gene DNA prime/recombinant adeno 5 vector boost vaccine in men & transgender women who have sex with men. Hancock G, Yang H, Frahm N, et al. The antiviral efficacy of CD8+ T cells in early HIV- 1 infection is dependent on targeting of low entropy regions of the viral proteome. Heit A, Schmitz F, Moore M, et al. HVTNtested candidate HIV vaccines induce early, antigen-specific plasmablast- and Tfh-like responses in peripheral blood. Hural J, Walsh S, Moodie Z, et al. Vaccination with heterologous HIV envelope sequences and heterologous adenovirus vectors increases T cell responses to conserved regions: HVTN 083. Karuna S, Andrasik M. Transgender participants in phase 1-2a trials of the HIV Vaccine Trials Network (HVTN): A descriptive analysis. Lemos MP, Lama JR, Karuna ST, et al. In men at risk of HIV infection, antibodies can reach the human foreskin epidermis at ratios similar to those in blood. Lemos MP, Karuna ST, Lama JR, et al. The inner foreskin of healthy men resembles inflamed epithelium and has features of a compromised skin barrier. Morris L, Mkhize NN, Hermanus T, et al. Boosting antibody responses with gp140 protein two years after DNA/MVA priming: Results from the HVTN 073E Phase I vaccine trial. Seaton KE, Yates NL, Williams WT, et al. Human HIV-1 vaccine induced antibody durability and Env IgG3 responses. For more complete presentation information, including live streaming of select sessions, please see http://www.vaccineenterprise.org/conference/2013/ 36 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 37

hvtn annual network award winners HVTN Annual Network Award Winners On May 7, 2013 in Washington DC, the HVTN honored individuals who perform outstanding work at our sites. HVTN Citizenship Award The HVTN Citizenship Award is given to individuals deserving special recognition for their consistent, reliable, and quality performance of CRS duties and activities. Charlie Gregor, Clinic Coordinator, Fenway Award Recipient: Charlie Gregor, Clinic Coordinator, Fenway Accolades for Charlie: Charlie is a very strong leader who is quick to recognize the accomplishment of others and often uses operational meetings to celebrate successes. He is a tireless advocate for vaccine research and really enjoys working on Network committees. Charlie is well-respected among his peers and is quick to offer support and guidance to other coordinators. I am consistently impressed with his ability to identify a problem and implement a system change to address the issue. No detail or procedure is too minor or unimportant. He is involved in all aspects of the HVTN trials at Fenway... It s a pleasure to work with him and we are very lucky to have him! Nils Rettby, Study Manager, Lausanne Award Recipient: Nils Rettby, Study Manager, Lausanne Accolades for Nils: Working with Nils is like driving a Porsche or using an Apple product for the first time. He is consistently organized, responsive, well-prepared, and professional. He represents his site for both the logistical and nitty-gritty detail involved in study implementation, but also exhibits the thoughtful consideration required to support [the] Community Advisory Board [CAB]. I am thoroughly impressed by how well Nils wears the many hats of his job, from CAB coordination to clinic coordination. He knows how to work with community members in a way that has them fully engaged and prepared for Network activities. As a CER [community educator/recruiter] he is reliable and consistent in communications to Core and in report submis- sions. He is always willing to help out fellow CERs and Core, if and when solicited. Nils is always available to help review materials that have been translated into French, he works to translate materials if necessary to make sure his CAB is able to have meaningful participation at the site level, in addition to helping at Network conferences to make sure all the French speakers who attend (from Haiti or Lausanne CAB) can have a meaningful experience. hvtn service award The HVTN Service Award recognizes individuals who have creatively responded to a particular challenge arising in their CRS work, and by which value has been added to the CRS / HVTN enterprise. Vic Sorrell, Community Educator/Recruiter, Nashville Award Recipient: Vic Sorrell, Community Educator/Recruiter, Nashville Accolades for Vic: Vic was hired in 2010 specifically to coordinate outreach, education, and recruitment for HVTN 505. He quickly became an expert in the area of community outreach for our program he developed and coordinated an effort now well-known as "Karaoke for CARES." This is a series of events where singers compete at local clubs over the course of several months. Funds raised by donations (which counted as "votes") for each singer supported our local HIV/AIDS service organization, Nashville CARES. Karaoke for CARES was successfully operationalized in 2011 and 2012, shared with and duplicated by other HVTN sites, and provided a platform where our HVTN site not only gained support but showed support for the community. This led to networking not previously accomplished at our site and undoubtedly contributes to our successful recruitment and retention in HVTN 505. Karaoke for CARES is a major undertaking that required a great deal of creativity, effort, and dedication. In addition, Vic was just named "Inspirational Person of the Year" by Out and About Magazine in Nashville! hvtn mentoring award The HVTN Mentoring Award recognizes an individual who has demonstrated extraordinary commitment as a mentor, by promoting research, training/ education, and professional development of those they have mentored. Dr. Beryl Koblin, Principal Investigator, Union Square & Bronx Award Recipient: Dr. Beryl Koblin, Union Square & Bronx Accolades for Beryl: Beryl is an extraordinary mentor for trainees at all levels we are so fortunate as a network to be able to rely on Beryl as a dedicated investigator and colleague who takes the time to nurture the next generation of vaccine and prevention scientists with intelligence and warmth. Dr. Koblin has shown an ongoing and steadfast commitment to mentoring, as exemplified in her participation with the HVTN Research and Mentoring Program (RAMP) for Black and Latino Medical Students there is nothing better than seeing someone invest in the next generation of research scientists by mentoring [and] teaching others how to mentor. Beryl has continued to provide the Network with her expertise in the community and in the research world in a quiet and unassuming manner. She has a wealth of knowledge and is willing to share it with all. Octavio Valente, Jr. Volunteer Service Award Octavio Valente, Jr. was a dedicated CAB member from Rio de Janeiro, Brazil who passed away on March 21, 2006. Octavio served many roles in the HVTN and in the HIV/AIDS community through his advocacy, dedication and spirited energy. In his honor, this service award is given to a CAB member who has demonstrated exemplary leadership and dedication in the HVTN. Hamilton Richardson, CAB Member-at-Large, Baltimore Award Recipient: Hamilton Richardson, CAB Member-at-Large, Baltimore Accolades for Hamilton: Hamilton stands out for the longevity of his involvement, and his unbending willingness to step up whenever he is asked. He has been devoted to community advocacy for clinical HIV research and for people living with HIV and AIDS for many years...it is not sufficient to simply list the positions Ham has held, but rather, it is necessary to say that he has been a vocal and active leader in every position he has held. Hamilton has a tremendous heart and most importantly, the strength of his convictions: he is totally unafraid to speak out for what he believes to be right. For that, the HVTN and people living with HIV and AIDS everywhere are quite fortunate, and the HVTN thanks him profusely for all that he has done and will continue to do. 38 OCTOBER 2013 VOLUME 5:1 HVTNEWS www.hvtn.org HVTNEWS VOLUME 5:1 OCTOBER 2013 39

EDITOR-IN-CHIEF: cecilia morgan MANAGING EDITOR: adi ferrara senior SCIENCE WRITER: tracey day ILLUSTRATION & layout: lisa donohue distribution coordinator: jana pitzer FOR MORE INFORMATION, VISIT: hvtn.org Thank you to: Blythe Adamson, Alex Berger, Gail Broder, Danna Flood, Matthew Kirts, Courtney Liebi, Allison Northrop, Erik Schwab COMMENTS/QUESTIONS? HVTNews@hvtn.org Tel: 206 667-6300 Fax: 206 667-6366 HVTN/FHCRC, 1100 Fairview Ave North, E3-300 Seattle, Washington 98109-1024 For current and archived editions of HVTNews, please visit us here - hvtn.org Mission of the HVTN To enhance the discovery and drive the development of a safe and globally effective vaccine to prevent HIV. We do this through well-designed clinical research trials that objectively and ethically address the critical questions of the field. Our objective clinical trial platform lets us evaluate safety, immunogenicity and efficacy of candidate vaccines, as well as design clinical trials that will provide clues on ways to enhance the effectiveness of new vaccines. We promote the use of new innovations, which may help us get closer to a safe and effective vaccine more quickly. Calendar hvtn conference october 23-25, 2013 The Westin Cape Town, South Africa keystone symposia: hiv vaccines (joint with hiv pathogenesis) february 9-14, 2014 Fairmont Banff Springs Banff, Alberta, Canada conference on retroviruses and opportunistic infections (croi) march 3-6, 2014 Hynes Convention Center Boston, Massachusetts, USA hvtn conference june 3-5, 2014 Omni Shoreham Hotel Washington DC, USA 20th international aids conference july 20-25, 2014 Melbourne Convention and Exhibition Centre Melbourne, Australia The HIV Vaccine Trials Network is an international collaboration of scientists and educators. Support for the HVTN comes from the National Institute of Allergy and Infectious Diseases (NIAID) of the U.S. National Institutes of Health, an agency of the U.S. Department of Health and Human Services. The Network and NIAID have a close, cooperative working relationship, with shared attention to intellectual and scientific issues. 2013 HIV Vaccine Trials Network. All rights reserved.