Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial

Aponte, John J.; Aíde, Pedro; Renom, Montse; Mandomando, Inácio; Bassat, Quique; Sacarlal, Jahit; Manaca, Maria Nélia; Lafuente, Sarah; Barbosa, Arnoldo; Leach, Amanda; Lievens, Marc; Vekemans, Johan; Sigaùque, Betuel; Dubois, Marie‐Claude; Demoitié, Marie-Ange; Sillman, Marla; Savarese, Barbara; McNeil, John G.; Macete, Eusébio; Ballou, W. Ripley; Cohen, Joe; Alonso, Pedro L.

doi:10.1016/s0140-6736(07)61542-6

Cited by 250 publications

(171 citation statements)

References 13 publications

Supporting

Mentioning

161

Contrasting

Unclassified

Order By: Relevance

“…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

636

352

View full text Add to dashboard Cite

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

636

352

View full text Add to dashboard Cite

“…Radiation-attenuated, sporozoite-mediated sterile protection has served as a paradigm to guide the search for a recombinant preerythrocytic vaccine candidate but was not considered a viable solution to malaria vaccine development until recently (6). Yet, a vaccine against the parasite is not available, and the most advanced recombinant vaccine, RTS/S, which is based on the CS protein, conferred significant but limited protection against infection (26,27). A significant breakthrough toward feasibility of a liveattenuated malaria vaccine was the demonstration of genetic attenuation by gene deletions in rodent malaria models.…”

Section: Discussionmentioning

confidence: 99%

Preerythrocytic, live-attenuated Plasmodium falciparum vaccine candidates by design

VanBuskirk

O'Neill

Vega

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

155

150

View full text Add to dashboard Cite

Falciparum malaria is initiated when Anopheles mosquitoes transmit the Plasmodium sporozoite stage during a blood meal. Irradiated sporozoites confer sterile protection against subsequent malaria infection in animal models and humans. This level of protection is unmatched by current recombinant malaria vaccines. However, the live-attenuated vaccine approach faces formidable obstacles, including development of accurate, reproducible attenuation techniques. We tested whether Plasmodium falciparum could be attenuated at the early liver stage by genetic engineering. The P. falciparum genetically attenuated parasites (GAPs) harbor individual deletions or simultaneous deletions of the sporozoiteexpressed genes P52 and P36. Gene deletions were done by double-cross-over recombination to avoid genetic reversion of the knockout parasites. The gene deletions did not affect parasite replication throughout the erythrocytic cycle, gametocyte production, mosquito infections, and sporozoite production rates. However, the deletions caused parasite developmental arrest during hepatocyte infection. The double-gene deletion line exhibited a more severe intrahepatocytic growth defect compared with the single-gene deletion lines, and it did not persist. This defect was assessed in an in vitro liver-stage growth assay and in a chimeric mouse model harboring human hepatocytes. The strong phenotype of the double knockout GAP justifies its human testing as a whole-organism vaccine candidate using the established sporozoite challenge model. GAPs might provide a safe and reproducible platform to develop an efficacious whole-cell malaria vaccine that prevents infection at the preerythrocytic stage.genetically attenuated parasites ͉ malaria vaccine ͉ P36 ͉ P52 ͉ sporozoite M alaria is a formidable global health problem, affecting 300 million to 500 million people worldwide annually (1). The resulting Ϸ1 million deaths per year are mainly caused by Plasmodium falciparum infections. Eradication of malaria will in large part depend on an effective vaccine that prevents infection by Plasmodium, but such a vaccine has remained elusive. The parasites' preerythrocytic stages, encompassing the mosquito-inoculated sporozoites and liver stages that develop from sporozoites after their invasion of hepatocytes, are attractive targets for antiinfection vaccines, because at this stage the number of infected host cells is low, and further transmission of the parasite is not yet possible. Occurrence of blood-stage infection after sporozoite challenge is completely preventable by immunization with radiation-attenuated sporozoites in mouse models of malaria (2). This was a landmark finding that set the standards for malaria preerythrocytic vaccine development. Radiation-attenuated sporozoites arrest in development during hepatocyte infection, but their safety and efficacy are dependent on a precise irradiation dose. Humans immunized with P. falciparum radiation-attenuated sporozoites have been effectively protected from subsequent challenge with homologous an...

show abstract

“…Although many candidate vaccines are in development [10], only the RTS,S antigen formulated with either the AS01 or the AS02 Adjuvant System consistently confers partial protective immunity against infection by the P. falciparum parasite in malaria-naive ( [11][12][13], Kester, unpublished) and malaria endemic populations ( [14,15], Polhemus, unpublished), and in one trial, reduced clinical and severe malaria in young African children for 18 months [15,16]. Most recently, RTS,S/AS02 given in an Expanded Programme on Immunization compatible schedule at 10, 14, and 18 weeks of age was shown for the first time to protect infants against infection and clinical malaria for a 3-month period [17].…”

Section: Introductionmentioning

confidence: 99%

Phase 2a trial of 0, 1, and 3 month and 0, 7, and 28 day immunization schedules of malaria vaccine RTS,S/AS02 in malaria-naïve adults at the Walter Reed Army Institute of Research

Kester

Cummings

Ockenhouse

et al. 2008

Vaccine

Self Cite

121

View full text Add to dashboard Cite

K.E. Kester et al.against falciparum malaria would be compatible with the Expanded Programme on Immunization, or in combination with other prevention measures, interrupt epidemic malaria or protect individuals upon sudden travel to an endemic area. Methods:We conducted an open label, Phase 2a trial of two different full dose schedules of RTS,S/AS02 in 40 healthy malaria-naïve adults. Cohort 1 (n = 20) was immunized on a 0, 1, and 3 month schedule and Cohort 2 (n = 20) on a 0, 7, and 28 day schedule. Three weeks later, 38 vaccinees and 12 unimmunized infectivity controls underwent malaria challenge. Results: Both regimens had a good safety and tolerability profile. Peak GMCs of antibody to the circumsporozoite protein (CSP) were similar in Cohort 1 (78 g/mL; 95% CI: 45-134) and Cohort 2 (65 g/mL; 95% CI: 40-104). Vaccine efficacy for Cohort 1 was 45% (95% CI: 18-62%) and for Cohort 2, 39% (95% CI: 11-56%). Protected volunteers had a higher GMC of anti-CSP antibody (114 g/mL) than did volunteers with a 2-day delay (70 g/mL) or no delay (30 g/mL) in the time to onset of parasitemia (Kruskal-Wallis, p = 0.019). A trend was seen for higher CSP-specific IFN-␥ responses in PBMC from protected volunteers only in Cohort 1, but not in Cohort 2, for ex vivo and for cultured ELISPOT assays. Conclusion: In malaria-naïve adults, the efficacy of three-dose RTS,S/AS02 regimens on either a 0, 1, and 3 month schedule or an abbreviated 0, 7, and 28 day schedule was not discernibly different from two previously reported trials of two-dose regimens given at 0, 1 month that conferred 47% (95% CI: −19 to 76%) protection and in another trial 42% (95% CI: 5-63%). A strong association of CSP-specific antibody with protection against malaria challenge is observed and confirms similar observations made in other studies. Subsequent trials of adjuvanted RTS,S in African children and infants on a 0, 1, and 2 month schedule have demonstrated a favorable safety and efficacy profile.

show abstract

Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial

Cited by 250 publications

References 13 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

Preerythrocytic, live-attenuated Plasmodium falciparum vaccine candidates by design

Phase 2a trial of 0, 1, and 3 month and 0, 7, and 28 day immunization schedules of malaria vaccine RTS,S/AS02 in malaria-naïve adults at the Walter Reed Army Institute of Research

Contact Info

Product

Resources

About