Safety and Immunogenicity of RTS,S/AS02D Malaria Vaccine in Infants

Abdulla, Salim; Oberholzer, Rolf; Juma, Omar; Kubhoja, Sulende; Machera, Francisca; Membi, Christopher; Omari, Said; Urassa, Alwisa; Mshinda, Hassan; Jumanne, Ajuza; Salim, Nahya; Shomari, Mwanjaa; Aebi, Thomas; Schellenberg, David; Carter, Terrell; Villafana, Tonya; Demoitié, Marie Ange; Dubois, Marie-Claude; Leach, Amanda; Lievens, Marc; Vekemans, Johan; Cohen, Joe; Ballou, W. Ripley; Tanner, Marcel

doi:10.1056/nejmoa0807773

Cited by 206 publications

(149 citation statements)

References 10 publications

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“…3 Although the titer of anti-circumsporozoite antibodies is not an established correlate of the level of protection, an association with efficacy has been observed in several trials. [17][18][19][20][21] Infants may have mounted a lower immune response than older children owing to coadministration of RTS,S/AS01 with routine EPI vaccines, an inhibitory effect of maternally derived anti-circumsporozoite antibodies, an absence of priming with hepatitis B vaccine or with P. falciparum infection, or the infant's immature immune system.…”

Section: Discussionmentioning

confidence: 99%

A Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Infants

Agnandji¹,

Lell²,

Fernandes³

et al. 2012

N Engl J Med

625

352

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Section: Discussionmentioning

confidence: 99%

A Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Infants

Agnandji¹,

Lell²,

Fernandes³

et al. 2012

N Engl J Med

625

352

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“…The RTS,S malaria vaccine candidate provides partial protection against clinical malaria in African children, which has been repeatedly demonstrated in Phase IIb and Phase III clinical trials (1)(2)(3)(4)(5). The RTS,S target is the Plasmodium falciparum circumsporozoite protein (CSP), and it has been shown to generate high antibody titers that remain above levels acquired naturally for years (6).…”

mentioning

confidence: 99%

RTS,S Vaccination Is Associated With Serologic Evidence of Decreased Exposure to Plasmodium falciparum Liver- and Blood-Stage Parasites*

Campo

Aponte

Skinner

et al. 2015

Molecular & Cellular Proteomics

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The leading malaria vaccine candidate, RTS,S, targets the sporozoite and liver stages of the Plasmodium falciparum life cycle, yet it provides partial protection against disease associated with the subsequent blood stage of infection. Antibodies against the vaccine target, the circumsporozoite protein, have not shown sufficient correlation with risk of clinical malaria to serve as a surrogate for protection. The mechanism by which a vaccine that targets the asymptomatic sporozoite and liver stages protects against disease caused by blood-stage parasites remains unclear. We hypothesized that vaccination with RTS,S protects from blood-stage disease by reducing the number of parasites emerging from the liver, leading to prolonged exposure to subclinical levels of blood-stage parasites that go undetected and untreated, which in turn boosts pre-existing antibody-mediated blood-stage immunity. To test this hypothesis, we compared antibody responses to 824 P. falciparum antigens by protein array in Mozambican children 6 months after receiving a full course of RTS,S (n ‫؍‬ 291) versus comparator vaccine (n ‫؍‬ 297) in a Phase IIb trial. Moreover, we used a nested case-control design to compare antibody responses of children who did or did not experience febrile malaria. Unexpectedly, we found that the breadth and magnitude of the antibody response to both liver and asexual bloodstage antigens was significantly lower in RTS,S vaccinees, with the exception of only four antigens, including the RTS,S circumsporozoite antigen. Contrary to our initial hypothesis, these findings suggest that RTS,S confers protection against clinical malaria by blocking sporozoite invasion of hepatocytes, thereby reducing exposure to the blood-stage parasites that cause disease. We also found that antibody profiles 6 months after vaccination did not distinguish protected and susceptible children during the subsequent 12-month follow-up period but were strongly associated with exposure.

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“…The most advanced candidate malaria vaccine, RTS,S, is a pre-erythrocytic CSP-based sub-unit vaccine. Phase II trials of RTS,S/AS have demonstrated significant efficacy against time to first infection across all ages [4,37,38]. The principal component of RTS,S is the circumsporozoite antigen that induces high anti-CSP IgG antibody titres [10,36,39] and moderate CSP-specific T-cell responses [36,40,41] in vaccinated humans.…”

Section: Discussionmentioning

confidence: 99%

Efficacy model for antibody-mediated pre-erythrocytic malaria vaccines

et al. 2010

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Antibodies to the pre-erythrocytic antigens, circumsporozoite protein (CSP), thrombospondin-related adhesive protein (TRAP) and liver-stage antigen 1, have been measured in field studies of semiimmune adults and shown to correlate with protection from Plasmodium falciparum infection. A mathematical model is formulated to estimate the probability of sporozoite infection as a function of antibody titres to multiple pre-erythrocytic antigens. The variation in antibody titres from field data was used to estimate the relationship between the probability of P. falciparum infection per infectious mosquito bite and antibody titre. Using this relationship, we predict the effect of vaccinations that boost baseline CSP or TRAP antibody titres. Assuming the estimated relationship applies to vaccineinduced antibody titres, then single-component CSP or TRAP antibody-mediated pre-erythrocytic vaccines are likely to provide partial protection from infection, with vaccine efficacy of approximately 50 per cent depending on the magnitude of the vaccine-induced boost to antibody titres. It is possible that the addition of a TRAP component to a CSP-based vaccine such as RTS,S would provide an increase in infection-blocking efficacy of approximately 25 per cent should the problem of immunological interference between antigens be overcome.

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Safety and Immunogenicity of RTS,S/AS02D Malaria Vaccine in Infants

Abstract: Please refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alternatively contact researchonline@lshtm.ac.uk. Available under license: Copyright the publishersT h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med 359;24 www.nejm

Cited by 206 publications

References 10 publications

A Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Infants

A Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Infants

RTS,S Vaccination Is Associated With Serologic Evidence of Decreased Exposure to Plasmodium falciparum Liver- and Blood-Stage Parasites*

Efficacy model for antibody-mediated pre-erythrocytic malaria vaccines

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