Status of Vaccine Research and Development of Vaccines for RSV Prepared for WHO PD-VAC Date submitted: June 30, 2014

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1 Status of Vaccine Research and Development of Vaccines for RSV Prepared for WHO PD-VAC Date submitted: June 30, 2014 I. About the Disease and Pathogen Basic information on pathogen, including transmission, estimated global disease burden for those at risk, for morbidity and for mortality, including uncertainties/data gaps, geographical distribution, economic burden if available, age groups affected and target groups for vaccination. Existing preventive, diagnostic and treatment measures and their limitations. Respiratory syncytial virus (RSV) is the single most important cause of lower respiratory tract illness in infants <1 year of age, responsible for one-third of deaths in the first year of life. RSV causes repeat infections throughout life and significant disease in pediatric and elderly populations worldwide. The agent is an enveloped, non-segmented, single-stranded, negative-sense RNA pneumovirus belonging to the family Paramyxoviridae. The viral genome consists of ten genes encoding eleven proteins. Important surface proteins include the fusion (F) and attachment (G) glycoproteins, which are the only viral proteins that induce RSV neutralizing antibody. 1 The virus circulates seasonally in temperate regions, usually between late fall and early spring, lasting 3-4 months in a community, though timing varies between years, regions, and even communities. In tropical regions, the seasonal relationship is less well defined with virus detectible year round. Infection results from direct and indirect contact with nasal or oral secretions from infected persons. The annual global burden of RSV illness is significant, with 33.8 million estimated new episodes of RSVassociated acute lower respiratory infection (ALRI) worldwide in children younger than 5 years of age, and at least 3.4 million hospital admissions associated with severe RSV disease. Global mortality was estimated at 253,500 deaths in 2010, 2 with most occurring in developing countries. The RSV mortality rate is difficult to accurately assess in many countries and further complicated by an appreciable number of deaths that occur outside of medical treatment, likely resulting in under-reporting. The epidemiology and burden of RSV disease suggest there are several distinct target populations for RSV vaccines: 1) infants <6 months of age, at highest risk of severe disease; 2) children 6 months of age, both to prevent their disease and potential transmission to younger children and the elderly; 3) pregnant women, to protect newborns both by placental transfer of antibodies and by blocking transmission; and 4) the elderly. 3 RSV is also a significant concern for the other higher-risk members of the community such as healthcare and daycare workers, the immunocompromised, and individuals with pulmonary conditions or congenital heart disease. There are several overarching RSV diagnostic categories (cell culture, nucleic acid amplification, and immunofluorescence assays) in use today with countless variations on format, specimen preparation, and assay read-out. Rapid antigen detection test platforms (RADTs), considered a point-of-care diagnostic tool, are generally easy-to-use, cost less, and provide results within minutes. These assays tend to have low sensitivity, specificity, and yield only qualitative results. More complex and time-consuming microbiological and molecular laboratory-based platforms show high sensitivity and specificity, but most tests are technically challenging, time consuming, and require experienced, specialized personnel. While vaccines are among the most cost-effective health interventions, no vaccines against RSV are currently available. Treatment is usually reserved for patients with ALRI. Options for supportive care include supplemental oxygen and mechanical ventilation as well as pharmacotherapy with bronchodilators, corticosteroids, and ribavirin. Immunoprophylaxis with the neutralizing monoclonal Status of RSV Vaccine R&D Page 1

2 antibody palivizumab is used in the United States and certain other high-resource countries to prevent RSV disease in high-risk infants, but both monthly administration requirements and cost limit this option in resource-constrained settings. II. Overview of Current Efforts A. EITHER Vaccines currently available and their limitations OR Biological feasibility for vaccine development Include perceived limitations with available vaccines for low and middle income country markets (LMIC). These could include safety, effectiveness, serotype/strain coverage, supply, affordability, financing, number of WHO prequalified vaccines, WHO policy recommendations for available vaccines, perceived lack of priority from endemic country authorities. Where there are no vaccines available, this section should focus on the evidence that vaccine development is biologically feasible including from development of naturally acquired immunity, from vaccine development for related pathogens, from animal models or in vitro data. Several observations support the biological feasibility for RSV vaccine development: Primary RSV infection occurs in most infants in the first year of life, with all children infected by 3 years of age. Infections recur throughout life but as natural immunity builds, disease severity lessens until immunosenescence reverses the trend later in life. The ability of RSV-specific functional antibodies to neutralize viral infection has been demonstrated in vitro, and protection has been shown in numerous preclinical models (murine, guinea pig, calf, and primate), including a well-established cotton rat infection model. 4 Furthermore, monoclonal and polyclonal RSV antibodies delivered prophylactically to children reduces the incidence of severe RSV disease. 5 A reduced incidence of RSV disease during the first several months after birth correlates with higher concentrations of RSV-specific maternal antibody. Live-attenuated as well as inactivated virus vaccines have been successfully developed for influenza, a respiratory virus with many similarities to RSV in terms of viral and disease characteristics. Constraints on RSV vaccine development: RSV vaccine development is notable for the vaccine enhanced illness that occurred after a formalininactivated RSV (FI-RSV) vaccine was administered to seronegative infants in the 1960s. The serious illness and severe lung inflammation that occurred in vaccinees raised concerns that other candidate vaccines against RSV might also predispose young infants to aberrant immune responses. Immunization of older children with the FI-RSV vaccine did not result in enhanced disease, suggesting that prior infection had established a safe immune response pattern. The legacy of vaccine enhanced disease has left developers leery of using subunit vaccines in infants, consequently, only live vaccines have been tested for active infant immunization for the last 45+ years. B. General approaches to vaccine development for this disease for low and middle income country markets What are the scientific approaches and indications and target/age/geographic groups being pursued? What public health needs will these vaccines meet if successfully developed? Where there are several different possible indications/target groups, how much consensus is there as to prioritization between these for vaccine development in LMIC. Status of RSV Vaccine R&D Page 2

3 Recently, the RSV vaccine field has gained momentum and now has multiple candidates spread across the following platforms: Live-attenuated and live-vectored vaccines to protect pediatric populations from RSV disease have been in development for decades, and do not appear to cause enhanced disease in RSV naïve infants. Protein-based vaccine approaches including whole-inactivated virus, particle-based approaches, and subunit antigens have been targeted for protecting elderly populations from severe disease, often formulated with adjuvant. More recently, particle and subunit approaches are being developed to boost maternal antibody during pregnancy, naturally transferring protection to their infants, though these candidates will likely be more acceptable either unadjuvanted, or adjuvanted only with alum considering the sensitive target population. Gene-based Alphavirus, Adenovirus, Sendai virus, and MVA vectors encoding RSV antigens, including replication competent and deficient variations, are being targeted to protect infant and pediatric populations. Gene expression is expected to mimic natural infection resulting in authentic protein structures to elicit relevant antibody and cellular immunity, avoiding the potential for an aberrant response to processed vaccine antigens. Nucleic acid vaccines using either plasmid DNA or messenger RNA encoding RSV antigens are being targeted to protect both pediatric and elderly populations. For low- and middle-income countries (LMICs), a focus on reducing the incidence and severity of RSVrelated acute lower airway infection in children <5 years of age through vaccination would directly and positively impact Millennium Development Goal 4 (reducing child mortality). 6 In these settings, the prevalence of children infected with HIV and other chronic infections contributes to higher hospitalization rates and poorer outcomes in children with RSV disease. 7 A RSV vaccine strategy could result in fewer hospitalizations and lower morbidity, particularly in resource-constrained countries where access to medical care is often difficult and the cost of care a significant burden to parents. To successfully address the broad <5 population, allowing for adequate protection in the very young and immune persistence in older children, vaccine development will likely need a two-pronged approach, dividing the target population into two age groups: <6 months of age and >6 months. Severe RSV incidence is highest in infants younger than 5 months of age. The need for immediate protection and the difficulty of achieving protective efficacy via active immunization in this timeframe has led to consideration of a maternal immunization strategy to protect young infants. The goal is to delay acquisition of primary RSV infection until infant airways are larger, the immune system matures, and to reduce severity of disease if infection does occur. The approach may also protect against hypothesized vertical transmission in utero. 8 This strategy would be followed by direct older infant/child vaccination as maternal antibody wanes. Numerous live-attenuated and live-vectored RSV vaccine approaches to protect infants and children from RSV disease are being developed. Ensuring proper attenuation and stability, with appropriate immunogenicity, while overcoming perceived safety issues for this sensitive target population is paramount and has not yet been achieved. A live vaccine approach targeted to older infants and young children could ultimately complement a maternal immunization approach by protecting those older populations and decreasing transmission of the virus. This would bypass the challenge of adequate attenuation of live candidates for newborns that has been difficult to achieve. Aligned with reducing the burden of childhood pneumonia, strong consensus exists that the first 6 months of life carries the highest burden of severe RSV associated respiratory disease. Therefore, targeting maternal immunization would be a priority. Whether maternal immunization could assist with protection of preterm infants would need to be an area of investigation. Although highly important, the effectiveness of a maternal vaccination strategy is limited to the very young and would not provide protection for Status of RSV Vaccine R&D Page 3

4 children beyond ~4-6 months of age. In children with respiratory complications (asthma, congenital heart disease, bronchopulmonary dysplasia, cystic fibrosis, etc.) vaccination against RSV could be highly protective against RSV infection. While reports show up to 50% of children who experience severe RSV bronchiolitis have a subsequent asthma diagnosis, it s not clear which is cause or effect, and a RSV vaccine may help answer these questions. 9 Such a vaccination strategy may also help reduce secondary complications of bacterial infections following lower respiratory tract infections caused by RSV. III. Technical and Regulatory Assessment Highlight perceived positive/negative aspects in clinical/regulatory pathways eg well established product development and regulatory pathway to licensure, accepted immune correlates and/or functional assays, accepted surrogate efficacy endpoints, existence of well accepted animal or challenge models, agreed trial designs and endpoints. Possibilities to develop case for correlates/surrogates should be included. The regulatory pathway for RSV would follow standard vaccine development requirements, but with an increased safety focus early in development to evaluate enhanced disease given the earlier issues with FI- RSV vaccine. Adequate preclinical maternal immunization models have been established to allow advancement into the clinic (cotton rat, calf, baboon) and currently more than one vaccine program is advancing through Phase 1 or Phase 2 clinical trials. A commercial ELISA is available to evaluate immunogenicity of F and G proteins. Numerous assay formats have been developed to measure functional antibody against both RSV A and B subtypes. Recently, a binding competition assay using the prophylactic monoclonal antibody palivizumab has been developed to demonstrate that candidate vaccines induce antibodies binding to the same region of F protein recognized by an efficacious product. The binding competition assay shows promise as a useful tool, though it is limited to a single neutralizing epitope and doesn t ensure the competing antibodies are functional. A common standardized neutralization assay is the goal, but the ability of a single assay to appropriately evaluate the various vaccines in development remains to be demonstrated. In all instances, correlates of protection would ideally be established during Phase 3 efficacy trials which would be aimed at demonstrating reduction of severe RSV disease. Regulatory alignment on measurements of disease severity are important to allow advancement of vaccine programs. Developing and/or adopting severity scoring systems based on agreed upon measurements of respiratory compromise (e.g., level of hypoxemia, respiratory support requirements) will be important for advancing to licensure. Such scoring systems need to be applicable to varying settings where resource constraints may or may not alter the ability to provide supportive care and interventions. Endpoints for licensure should include reducing the most severe disease but can also consider reducing less severe disease where increased utilization of medical resources is measurable and deemed of important magnitude. Advancing to prequalification rapidly, once licensure is obtained, is critical as the most severe disease occurs in the countries with greater resource constraints. IV. Status of Vaccine R&D Activities Summarise status of vaccine design, pre-clinical and clinical trial activity, including platforms, vectors, adjuvants. Note academic, government, biotech and industry entities engaged. Summarise antigenic targets (if subunit approaches). Section on major advances in last 3-5 years, including key opportunities highlighted by recent science developments in the area. The success of RSV immunoprophylaxis confirms the rationale for generating functional antibody responses as a vaccine strategy. RSV F and G surface glycoproteins are targets for neutralizing antibody, and while antibodies to F protein are cross-reactive across RSV A and B subtypes, antibodies to G protein are much less so. Efficacy of palivizumab, based on antigenic site II of F protein provides further evidence of F-specific antibody protection, leading many developers to focus on RSV F as a vaccine antigen. Status of RSV Vaccine R&D Page 4

5 There are currently 51 RSV vaccine candidates in development encompassing 4 broad platforms. Live attenuated approaches have been in development for decades by NIAID and/or MedImmune, and until recently were the only candidates in clinical testing (Ph1 and Ph2). More recently there has been a significant surge in RSV vaccine development using other technologies. While the majority are still at the preclinical stage, 4 of these newer candidates have now entered clinical development Novavax (Ph2), GSK (Ph1), and MedImmune (Ph1) testing RSV F protein-based candidates and GSK (Ph1, 2013 acquisition of Okairos) testing an Adenovirus/MVA prime/boost candidate expressing RSV F, and a N and M2-1 fusion protein. Preclinical vaccine developers include pharma, government, academic, and biotech organizations targeting infant, child, and elderly populations (see Table 1). a. Live-attenuated and live-vectored 9 candidates b. Protein-based 26 candidates total i. Whole-inactivated virus 1 candidate ii. Particle-based 13 candidates iii. Subunit antigens 12 candidates c. Nucleic acid 4 candidates d. Gene-based vectors 10 candidates e. Combination of approaches 2 candidates Major advances in last 3-5 years: RSV F protein has significantly different pre-fusion (pre-f) and post-fusion (post-f) conformations. While the post-f form is very stable, the pre-f form is not. Successful stabilization of the pre-f conformation was accomplished in 2013, 10,11 enabling pre-f to be used as a vaccine antigen. A new antigenic site not found on the post-f form was identified, and antibodies to this site appear to be more potent than palivizumab. The success of a maternal immunization strategy will require access to and acceptability of vaccination in pregnant women. Platforms exist for vaccine delivery to pregnant women that leverage the likelihood that, even in the least-developed countries, the majority of women will have some antenatal care (WHO 2010). The successful global Maternal and Neonatal Tetanus Elimination Initiative, the recent recommendation by the WHO that pregnant women should be the highest priority group for influenza vaccine, and the recent recommendation for maternal immunization to protect infants from pertussis by the US Advisory Committee for Immunization Practices (ACIP) all provide important precedents for acceptance/justification of a maternal immunization approach. Several vaccine developers including Novavax, GSK, and Novartis are actively advancing RSV maternal vaccine candidates. Table 1: Development Status of Current Vaccine Candidates (POC = Proof of concept trial) Candidate Name/Identifier Preclinical Phase 1 Phase 2 POC Phase 3 Live-attenuated and live-vectored Codagenix- codon de-optimized RSV Emory- RSV Intravacc- ΔG RSV Pontifica Universidad Catolica de Chile- BCG expressing RSV NP or M2 St. Jude Children's Research Hospital/ Sendai-RSV chimera expressing RSV F protein Medimmune-NIH/NIAID/LID- RSV cps2 Status of RSV Vaccine R&D Page 5

6 Medimmune-NIH/NIAID/LID- RSV, Medi-RSV ΔM2-2 Medimmune- RSV, Medi-559 NIH/NIAID/LID- RSV ΔNS2 Δ1313 Whole-inactivated NanoBio- Whole RSV inactivated with oil-in-water nanoemulsion adjuvant Particle-based Agilvax- RSV F and G peptide antigens displayed on VLPs Artificial Cell Technologies- ACT 1190, layer-by-layer microparticles displaying RSV G and M2 conserved peptides Emory University- VLPs produced in insect cells with influenza M1 core, displaying RSV F or RSV G Fraunhofer- Plant-based production of VLPs displaying RSV G peptides or RSV F protein Georgia State University- VLP Mucosis- SynGEM, lactococcus bacteria-like particles displaying RSV F protein Mymetics- RSV virosomes containing adjuvant Novavax- RSV F protein nanoparticles produced in insect cells Ruhr-Universitat Bochum- VLP displaying RSV F protein Takeda (Ligocyte)- Enveloped VLPs displaying RSV F protein TechnoVax- VLPs produced in mammalian cells University of Massachusetts- Newcastle Disease Virus VLPs displaying RSV F and/or G proteins VLP Biotech- VLP displaying RSV F protein site II (palivizumab) epitopes Subunit GSK Vaccines- RSV F prefusion protein produced in CHO cells Immunovaccine- DP-RSV, DepoVax adjuvanted RSV surface protein Instituto de Salud Carlos III- RSV F stabilized pre-fusion protein MedImmune- MEDI17510, RSV F antigen plus adjuvant Status of RSV Vaccine R&D Page 6

7 NIH/NIAID/VRC- RSV F prefusion protein Novartis- RSV F post-fusion protein produced in CHO cells PeptiVir- Conformationally constrained RSV F peptides Renaptys- RSV Peptides University of Georgia- RSV G protein peptide or polypeptide University of Ghent- VIB/ Ectodomain of SH protein University of Illinois- Tomato plant expressing RSV F protein University of Saskatchewan- CHO produced RSV F protein + TLR agonist & host defense peptide in polyphosphazene microparticles Nucleic acid CureVac- RNA Inovio- DNA Novartis- Self-amplifying RNA encapsulated in a lipid nanoparticle Ruhr-Universitat Bochum- DNA encoding RSV F Gene-based vectors Alphavax- Replication-deficient VEE VRPs expressing RSV F AmVac- AMV601, 602, 603, semi-live adeno-virus vector coding for RSV proteins Bavarian Nordic- Replication-deficient pox virus (MVA) expressing RSV F and G proteins Crucell- Adenovirus GSK Vaccines (Okairos)- Replicationdefective PanAd3 and MVA expressing RSV F protein, and an N and M2-1 fusion protein RuenHuei Biopharmaceuticals- Replication-incompetent Ad3 vector expressing RSV F protein Ruhr-Universitat Bochum- Adenovirus vector coding for RSV F Vanderbilt University- Replicationdeficient VEE VRPs expressing RSV F or G protein University of Pittsburg/Baylor College of Medicine- Ad5 expressing RSV-F Emergent BioSolutions- MVA Status of RSV Vaccine R&D Page 7

8 Combination Biomedical Research Models- DNA prime, subunit boost Fudan University- DNA coding for RSV G co-delivered with RSV G protein References Key references including websites if desired. Keep to a core list, no more than Preferably 5 or less. 1. Dudas RA, Karron RA. Respiratory syncytial virus vaccines. Clin Microbiol Rev. Jul 1998;11(3): Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study Lancet. Dec ;380(9859): Anderson LJ, Dormitzer PR, Nokes DJ, Rappuoli R, Roca A, Graham BS. Strategic priorities for respiratory syncytial virus (RSV) vaccine development. Vaccine. Apr ;31 Suppl 2:B Connors M, Collins PL, Firestone CY, et al. Cotton rats previously immunized with a chimeric RSV FG glycoprotein develop enhanced pulmonary pathology when infected with RSV, a phenomenon not encountered following immunization with vaccinia--rsv recombinants or RSV. Vaccine. 1992;10(7): Groothuis JR, Hoopes JM, Hemming VG. Prevention of serious respiratory syncytial virus-related illness. II: Immunoprophylaxis. Adv Ther. Feb 2011;28(2): Nair H, Nokes DJ, Gessner BD, et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet. May ;375(9725): Moyes J, Cohen C, Pretorius M, et al. Epidemiology of respiratory syncytial virus-associated acute lower respiratory tract infection hospitalizations among HIV-infected and HIV-uninfected South African children, The Journal of infectious diseases. Dec ;208 Suppl 3:S Piedimonte G, Perez MK. Alternative mechanisms for respiratory syncytial virus (RSV) infection and persistence: could RSV be transmitted through the placenta and persist into developing fetal lungs? Current opinion in pharmacology. Jun 2014;16C: Bacharier LB, Cohen R, Schweiger T, et al. Determinants of asthma after severe respiratory syncytial virus bronchiolitis. The Journal of allergy and clinical immunology. Jul 2012;130(1): e McLellan JS, Chen M, Joyce MG, et al. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science. Nov ;342(6158): McLellan JS, Chen M, Leung S, et al. Structure of RSV Fusion Glycoprotein Trimer Bound to a Prefusion-Specific Neutralizing Antibody. Science. Apr Status of RSV Vaccine R&D Page 8