Will live oral vaccines work in children in the developing world? Martin Friede Ph.D. Initiative for Vaccine Research

Transcription

1 Will live oral vaccines work in children in the developing world? Martin Friede Ph.D. Initiative for Vaccine Research

2 Estimated global distribution of the 600,000 annual deaths caused by rotavirus 2 1 dot = 1000 deaths

3 Why live oral vaccines Oral delivery is supposed to be easy - Needle free - Minimal training of health care workers Mimics natural infection with replication (local immunity) Cheap (?) Sabin oral polio vaccine: the Gold Standard for simplicity and Practicality (or was it smallpox?) 3

4 However..There are Challenges Reduced immunogenicity in developing countries Susceptibility to gastric acid: need for complex formulation and delivery logistics Live: cold chain Number of doses Safety : reactogenicity excretion immunosupression reversion 4

5 Numerous oral vaccines have shown reduced immunogenicity in developing countries Sabin attenuated poliovirus Ty21a oral typhoid vaccine CVD 103-HgR live oral cholera vaccine BS/WCV (non-living cholera vaccine) Peru 15 live cholera vaccine SC 602 live Shigella flexneri 2a vaccine 5

6 Possible reasons for reduced efficacy in LDC populations Infants: Maternal antibody Breast milk antibodies Competing intestinal infection (Lagos et al, 1999) Environmental enteropathy Parasites and helminths (Cooper et al, JID 2000) Malnutrition Vit A, Zn defficiency Concomitant diseases (HIV, TB, malaria etc) 6

7 ENVIRONMENTAL ENTEROPATHY Normal Industrialized country infant Environmental Enteropathy Developing country infant From M. Levine 7

8 Effect of Infection Pressure on Typhoid Vaccine Efficacy* ite doses vaccine Efficacy % Burden in controls (per ) epal 1 Vi donesia 3 Ty21a Africa 1 Vi ietnam 2 Vi conj hile 3 Ty21a hile 3 Ty21a gypt 3 Ty21a hina 1 Vi *Adapted from Keith Klugma 8

9 Effect of Infection Pressure on Typhoid Vaccine Efficacy* ite doses vaccine Efficacy % Burden in controls (per ) epal 1 Vi donesia 3 Ty21a Africa 1 Vi ietnam 2 Vi conj hile 3 Ty21a hile 3 Ty21a gypt 3 Ty21a hina 1 Vi *Adapted from Keith Klugma 9

10 Effect of Infection Pressure on Typhoid Vaccine Efficacy* ite doses vaccine Efficacy % Burden in controls (per ) epal 1 Vi donesia 3 Ty21a Africa 1 Vi ietnam 2 Vi conj hile 3 Ty21a hile 3 Ty21a gypt 3 Ty21a hina 1 Vi *Adapted from Keith Klugma 10

11 IMMUNOGENICITY OF SINGLE-DOSE CVD 103-HgR LIVE ORAL HOLERA VACCINE IN HIGH AND LOW SOCIOECONOMIC LEVEL PERUVIAN ADULTS GMT: Group N SCN Pre Peak High SEL Placebo 41 10% CFU 40 75% CFU 40 83% Low SEL Placebo 38 3% CFU 39 51% CFU 39 77% Data from Gotuzzo E et al, Infect Immun 1993 CV 11

12 otavirus vaccines in developing countries Preliminary data suggests that they might not perform as well and we will need to figure this out soon! RIT Failed in Africa/Peru WC3 Failed in Africa RRV Lower efficacy in Peru/Brazil 12

13 ill the new vaccines work equally well in the developing world? To date, the immune responses to the GSK in infants has been: greatest in Finland (>90%) intermediate in Latin America (~70%), mediocre in S. Africa (~50%) and Bangladesh. Why is there a gradient in response? Will this correlate with efficacy? What can we to anticipate/prevent this? 13

14 Hypotheses Maternal antibodies inhibit vaccine take Do they inhibit the immune response to vaccine? Are maternal antibody titers higher among children in LDCs? Breast milk plays a role Inhibits response to vaccine (R Glass, et al. 1990) Is milk from LDC mothers different? What is the interval between feeding and vaccine? Underlying medical conditions Diarrhea/ malnutrition Host factors eg stomach acid Other factors the vaccine strains! 14

15 Breast Feeding Inhibits the immune response to vaccine R Glass, et al

16 How will the vaccines compare RotaRix Homologous strain Human P[8],G1 Lots of shedding >50% Great replication RotaTeq Heterologous strains Bovine Little shedding <5% Poor replication??? New candidate hich will work better in the developing-country infant gut? ill mucosal / systemic immunity differ? 16

17 The challenge for RV vaccines in LDC Inhibitory factors Window Maternal antibodies Breast milk Concomitant infections Risk of intussusception Natural infection age In least developed countries v. difficult to ensure vaccine given in narrow window 17

18 Rotavirus Formulations? 18

19 Effect of Formulation Volume in the cold chain Cost Incremental cost increase Pressure on other vaccines Logistics of reconstitution with antacid Yield during drying Packaging Compatible with multidose formats Ideal formulation for upstream candidates Heat stable How long? How hot? VVM Simple logistics of administration No reconstitution? Liquid? Lyotab? 19

20 One dose, two dose, three dose, more? In least developed countries DTP3 coverage low Compliance Compliance within tight time-frame Ideal is maximum protection with a single dose 20

21 Inactivated vaccines Systemic delivery (Requires injection) Needle-free injection devices Requires adjuvant Mouse data suggest that Th1 response needed for protection Immunity in presence of maternal antibodies? Number of doses? 21

22 Conclusions Essential that vaccines are tested in the populations that need them the most (least developed) Testing needs to take into account the reality of age-groups and behaviour that vaccine administration will face. Some RV vaccines may be more applicable for LDC populations than others Efficacy, safety across larger age-group Logistics: cold chain volume, weight, reconstitution, antacid, Upstream candidates must take this into account Until jury is out, research on backup strategies such as inactivated vaccines should continue 22

23 Acknowledgments WHO New Vaccine Delivery Systems Steering Committee (chaired by G. Dougan) Roger Glass Myron Levine 23