Norway facing challenges in vaccination research

Transcription

1 Norway facing challenges in vaccination research Vaccination programmes will not have the expected consequences in high-mortality countries unless we recognize that Vaccinations may have non-specific - beneficial or detrimental - effects on child survival Vaccinations may have sex-differential beneficial or detrimental effects Vaccinations may interact with other immune modulating or enhancing interventions Peter Aaby, Bandim Health Project, Guinea-Bissau

2 Demographic surveillance 1/3 of Bissau 200 villages in interior : Child mortality in Bissau 50% before 5 yrs of age. SAREC project to reduce mortality through reducing malnutrition => However, the children were not malnourished - Measles severe

3 Before-after measles vaccination: Annual mortality in African community studies 14% 12% 10% 8% 6% 4% 2% 0% Bissau 6-35 mo Bandafassi 9-60 mo, Senegal Niakhar 9-23 mo, Senegal Before After Zaire 7-21 mo Measles is not 50% of deaths Why this effect of Measles vaccine? Other interventions? Selection bias even RCT show effect

4 1998 war in Bissau. Children had been randomised to MV or control vaccine (IPV) at 6 mos all to receive MV at 9 months Mortality during the 3 months of the war in Bissau Measles vaccine Survival probability MR= 0.30 ( ) Without measles: 0.28 ( ) 2 IPV Not due to prevention against Age (months) measles infection => Non-specific effect of MV

5 Mid-1980s use of high-titre measles vaccine (HTMV) to protect early against measles infection. Bissau trial EZ=HTMV at 4 mo; IPV at 9 mo Control= IPV at 4 mo; MV at 9 mo 0.9 Control M EZ M Control F Survival probability EZ F EZ protective against measles => Non-specific deleterious effect Age (months)

6 High-titre measles vaccine, Senegal, Survival probability Con F EZ M Con M 0.80 EZ F Age (months) Withdrawn 1992 by WHO when also found on Haiti (and Sudan) Excess mortality was 35% => ½ mill deaths in Africa alone

7 No difference in protection against measles => Non-specific and Sex-differential effects M F We know boys and girls are different but we routinely treat them equally

8 Male and female mortality rates (%) before and after the introduction of measles vaccine (MV) for children aged 9 mo to 5 years. Bandafassi Before MV After MV F/M Mortality 1.04 ( ) 0.65 ( ) Boys Girls

9 SUDAN SENEGAL HAITI SENEGAL SENEGAL GAMBIA SENEGAL MALAWI + SEN Female/male mortality ratio Standard measles-vaccinated Female-male mortality Ratio

10 BCG OPV DTP/OPV measles DTP booster Birth wk 9 mo 18 mo Original vaccination schedule What about the other vaccines?

11 Interim: Trial of BCG vs no BCG at birth to low-birth weight infants Vaccine Mortality (Deaths/children enrolled) Until 12 months Before DTP After DTP BCG 6%(38/637) 4%(26/637) 3%(12/382) No BCG 9%(56/621) 7%(44/621) 3%(12/366) Ratio BCG vs no BCG 0.66 ( ) 0.58 ( ) 0.96 ( )

12 Introduction of DTP Rural areas Children aged 2-8 mo Followed 6 mo Unvaccinated: travelling; sick; days without vaccines DTP (N=868) Survival probability 0.94 DTP + (N=967) 0.92 DTP+ / DTP ( ) Follow-up (months)

13 Contrasting effects of BCG, DTP, and MV Mortality Ratio * * * * * * * * BMJ 2000 Benin Bissau-war DTP introduction Hospital fatality Malawi BCG DTP Measles V BMJ 2000: These trends are unlikely to be explained by selection biases since different vaccines were associated with opposite tendencies * Difference between two vaccines significant p <0.05

14 Case fatality during war in Bissau 1998 by last vaccine; children aged 1-18 mo 7% 6% 5% 4% 3% Boys Girls 2% 1% 0% DTP Measles Vaccine F/M mortality ratio: DTP 3.1 ( )

15 Female/male MR for DTP-vaccinated children SENEGAL SENEGAL SENEGAL GHANA GAMBIA SENEGAL MALAWI Girls have 60-70% higher Mortality than boys Female-male mortality Ratio

16 HTMV and DTP? 60 No DTP after HTMV 40 DTP after HTMV Number of deaths Number of deaths Girls Boys Senegal HT Senegal routine Bissau Gambia Sudan Zaire 0 Senegal HT Senegal Routine Bissau Gambia Sudan F/M ratio: 0.96 ( ) F/M ratio: 1.93( ) Withdrawn for the wrong reason?

17 Combined interventions I: Live and inactivated vaccines: Simultaneous DTP+MV versus MV alone Congo Malawi Bissau Gambia Senegal Ghana Study EZ-trial: 6-36 mo Community study Hospital fatality 6-17 mo; Vaccination cards from dead children Routine vaccination 9-24 mo; Routine vaccination MV+DTP vs MV 5.38 ( ) 5.27 (1.1-25) 1.87 ( ) 3.42 ( ) 2.21 ( ) 1.76 ( ) Matlab, Bangladesh: MR for MV: 0.93 ( ) MR for MV with censoring for DTP+BCG+MV: 0.61 ( ) => MV+BCG+DTP had 3-fold higher mortality than children with no MV

18 Conclusions vitamin A supplementation Also indications of sex-differences in response to vitamin A Our group is the only one which has consistently looked for sex-differences We have found them in all our studies so far Boys seem to benefit more from vitamin A supplementation than girls Vitamin A supplementation (VAS) associated with a 23-30% reduction in child mortality. Not explained by A deficiency

19 Combined interventions: Vitamin A (VAS) given with missing vaccines in children aged 6 to 18 months Relative mortali ty Vaccine group DTP MV No P=0.002 VAS and DTP associated with a mortality ratio of 3.5 compared with children receiving VAS alone

20 Asian studies have shown major reduction in infant mortality following vitamin A supplementation (VAS) at birth => Trial in Bissau => But no effect: 1.08 ( ) VAS with BCG at birth: mortality by sex Cumulative mortality Cumulative mortality in boys with DTP as last vaccine Age in months Cumulative mortality Cumulative mortality in girls with DTP as last vaccine Age in months lastvacvita = DTP Vitamin A lastvacvita = DTP Placebo lastvacvita = DTP Vitamin A lastvacvita = DTP Placebo All Boys Girls BCG (0-6 weeks) 0.87 ( ) 0.89 ( ) 0.83 ( ) DTP (6 weeks-8 months) 1.40 ( ) 0.90 ( ) 2.11 ( )

21 Norway facing challenges in vaccination research Vaccinations may have non-specific - beneficial or detrimental - effects on child survival Beneficial: MV, BCG, Vit A Detrimental: (HTMV), DTP, HBV, IPV, Vit A Vaccinations may have sex-differential beneficial or detrimental effects Live (good girls), inactive (bad girls), Vit A (good boys) Vaccinations may interact with other immune modulating or enhancing interventions Sequence of vaccines (HTMV+DTP), combinations (MV+DTP, BCG+DTP, BCG+OPV), micronutrients (Vit A+DTP)

22 Norway facing challenges in Vaccination Research Measles-vaccinated F/M mortality ratio DTP-vaccinated F/M mortality ratio SUDAN SENEGAL HAITI SENEGAL SENEGAL GAMBIA GHANA SENEGAL SENEGAL MALAWI + SEN SENEGAL SENEGAL SENEGAL GHANA GAMBIA SENEGAL MALAWI Female-male mortality Ratio Female-male mortality Ratio We need a new immunological theory, RCTs to test different options, optimisation of programmes for both sexes, and surveillance in high-mortality countries

23 Routine vaccinations The Bissau experience MU1 MU3 MU5 Mortality < 1 yr, < 3yr, and <5yr in Bissau 25 years

24 Parasitemia day 7 post-infection (D14) (Mean + SEM) % parasitised RBCs VAS + DTP p for VAS+DTP vs others = VAS + NaCl Control + DTP Control + NaCl Explain the underlying immunological mechanisms for NSE and sex-differential effects

25 Infant Mortality % 6 Combined interventions: Polio vaccine (OPV) and BCG at birth Boys Girls 1 0 OPV at birth No OPV at birth Boys had 3 fold higher mortality if receiving OPV at birth

26 Median IFN response to PPD P< NoBCG NoOPV BCG NoOPV NoBCG OPV BCG OPV

27 Hospital case fatality (%) 25% 20% 15% 10% Boys Girls 5% 0% BCG DTP MV DTP Booster F/M case fatality ratio inversion: BCG vs DTP DTP vs MV

28 The effect of vitamin A given with BCG on infant mortality according to sex. Guinea-Bissau Boys Girls Cumulative mortality Age in days Cumulative mortality Age in days Vitamin A Placebo Vitamin A Placebo Boys: 0.86 ( ) Girls: 1.36 ( )

29 Children randomised to measles vaccine or control vaccine (IPV) War in Bissau Measles vaccine Survival probability MR girls 0.0 (0-0.4) boys 1.02 ( ) 2 IPV Age (months) Standard MV has non-specific and sex-differential effects

30 BCG scar, TST and mortality Boys Scar TST Girls Scar TST Mortality rate ratio

31 The impact of DTP Guinea-Bissau Gambia Mortality rate (per 1000 years) Male Female Mortality rate (per 1000 years) Male Female Age (months) Bandwidth: 4 months Age (months) Bandwidth 4 months We have examined the sex-differential effects in data from Gambia, Senegal, Ghana, Sudan, Congo, Malawi, Bangladesh Increased female mortality in the age group of DTP vaccinations Early MV?

32 Hospital case fatality for children aged 1-8 months with DTP3 as last vaccine. Bissau 20% 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% DTP3 DTP3 Boys Girls World Bank, Gavi and Gates monitor vaccinations with DTP3

33 Mortality rate for children aged 1½-7½ mo and 7½-12 mo in different cohorts. Bissau Received HBV % ½ mo 7½-12 mo

34 Routine surveillance for vaccinations and vitamin A Vaccination card seen at home visits Vaccinations documented at health centres Vaccination card for hospitalised children Vaccination card collected at verbal autopsy Information collected from campaigns

35 Possible clinical trials to modify current vaccinations policy OPV at birth in Bissau VAS with vaccines in Bissau DTP+MV versus only MV - multicentre Other possibilities : BCG sufficient outreach? Early MV - require early DTP and measles surveillance?

36 Children whose death might be prevented by measles vaccine are...on the road to death, and their nutritional status is so poor that they are more likely to die of any infectious disease. Thus preventing a death with vaccine among these children may not necessarily save a life, but only change the cause of death (Mosley 1982) : Child mortality in Bissau 50% before 5 yrs of age. SAREC project to reduce mortality through reducing malnutrition => Nutritional surveys in interior and an urban area in Bissau

37 Problem: No severe malnutrition Measles case fatality rate: 21% < 5 yrs 120% 100% 80% 60% 40% 20% 0% Weight/age Height/age Weight/height Died of measles (60) All children (1188)

38 Overcrowding and intensive exposure 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Intensity of exposure: Case fatality in measles infection, Bissau mo mo mo Index Secondary

39 Index case: Infected outside the home (brief exposure) Secondary case: Infected in the home (intensive exposure)

40 Bissau: Annual mortality rate for children aged 6-35 months 14% 12% 10% 8% 6% 4% 2% 0% Measles vaccine Measles vaccine % received vaccination Total Measles vaccinated Not vaccinated

41 I: War in Bissau, Children had been randomised to measles vaccine or control vaccine (IPV) at 6 mos

42 Mortality ratio: BCG vaccinated vs unvaccinated children Benin: < 3yr Bissau: 0-8 mo Bissau: 0-6 mo Malawi: 0-8 mo Bissau: 0-6 mo Bissau: 0-8 mo

43 Studies from Indonesia and India showed major reduction in infant mortality following VAS at birth => We tested vitamin A given with BCG on infant mortality according to sex. Guinea-Bissau Boys Girls Cumulative mortality Age in days Cumulative mortality Age in days Vitamin A Placebo Vitamin A Placebo Boys: 0.86 ( ) Girls: 1.36 ( ) All children: 1.08 ( )

44 AEROPORTO BISSAU Bandim Health Project Rural study areas 10,000 to 70,000 VOLTA DE BISSAU ANTULA BONO ANTULA PLAQUE II HAFIA COCO PLUBA HOTEL Urban study area 6,200 to 92,000 BRA PENHA QUELELE BAIRRO MILITAR PLAQUE I CUNTUM MEDINA AJUDA II CUNTUM GRANJA / VETERINARIO MISSIRA BELEM BANDIM 1 LUANDA SINTRA NEMA MINDARA ROSSIO CALEQUIR PEFINE AMEDALAI REINO GAMBEAFADA VARELA ST. LUZIA CUPILON DE BAIXO CUPILON DE CIMA BANDIM 2 CHAO DE PAPEL CENTRO National hospital Simao Mendes TCHADA Personnel 10 to 150 CANAL DO GEBA WIM DEKKERS PSB, 1996 ILHEU DO REI Change between 1978 and 2006