This trial demonstrated that vaccination with two doses of DNA ME-TRAP followed by a single dose of MVA ME-TRAP is safe and highly immunogenic for effector T cell induction but that it did not reduce the P. falciparum
infection rate in a semi-immune adult African population. This provides a second comparison between protection in malaria-naïve and malaria-experienced adults. RTS,S/AS02, a circumsporozoite protein malaria vaccine based on a hepatitis B surface antigen virus-like particle formulated in a proprietary adjuvant, provided about 40% sterile protection in the artificial challenge model [29
] and 71% short-term protection against natural infection [30
]. The lack of field efficacy found in the present study despite evidence of partial protection in United Kingdom volunteers supports the use of complete, not partial, protection in the sporozoite challenge model as a predictor of likely field efficacy against malaria infection when screening pre-erythrocytic vaccine candidates. However, some vaccines are known to prevent disease but not infection, as is also the case for naturally acquired immunity to malaria. There was no effect of bednet use on parasitaemia in either this study or an earlier malaria vaccine trial in adults [30
], whereas bednet use has been found to substantially reduce the incidence of clinical malaria and childhood mortality in Gambian children [31
]. The present study does not exclude the possibility that the vaccination regimen tested could provide significant anti-disease immunity. Paediatric study designs are necessary to evaluate this possibility. The present study highlights an issue related to use of surrogate efficacy endpoints; whereas positive results can spur development, negative results may incorrectly lead to the cessation of development of a candidate vaccine.
Another possible reason for the observed low efficacy is that the frequency of the effector T cell response declines from 7 d after boost, and so efficacy would be prevented if very high frequencies of circulating effectors are needed for protective efficacy. Alternatively, a suboptimal regional memory T cell pool in the liver may be responsible [32
], or, less likely in view of the observed T cell strain cross-reactivity, TRAP polymorphisms may have impaired T cell recognition.
In previous studies in East and West Africa, summed T cell responses to TRAP in unvaccinated semi-immune adults by ex vivo γ-interferon ELISPOT were geometric mean less than 20 SFCs per million PBMCs. The candidate regimen represents a new method for induction of unprecedented effector T cell frequencies, which are about 50-fold higher than those induced by lifelong natural exposure. Estimates of the reduction in liver-stage parasite burden induced by these vaccines in the human challenge model are of the order of 80%–90% of infected hepatocytes [21
]. It is unclear whether a similar level of anti-parasite activity could have been achieved in this study without any significant change in infection rate. Another candidate malaria vaccine that reduced liver parasite burden by an estimated 95% in challenge studies [29
] did have a substantial, if short-lived, impact on infection rates in a similar Gambian field study [30
]. This suggests that a moderate increase in the efficacy of this first-generation prime-boost vaccination strategy in reducing liver parasite burden might have an important impact on overall efficacy.
Second-generation prime-boost vaccine strategies for malaria currently in or near to clinical evaluation include the following: use of a different viral vector as the priming agent that may lead to proportionately greater CD8+ rather than CD4+ T cell induction (J. M. Vuola, S. Keating, D. P. Webster, T. Berthoud, S. Dunachie, et al., unpublished data), as is the case with fowlpox-MVA immunisation; the use of a different antigen, the circumsporozoite protein, or polyprotein constructs [34
] to address the difficult issue of target antigen selection; and evaluation of regimes that seek to combine high-level T cell responses with strong anti-sporozoite antibody induction, e.g., protein/adjuvant and recombinant virus prime-boost immunisation. In the medium term, combination with protective blood-stage antigens is also desirable. Determining methods for the successful combination of different candidate vaccine regimens (whether within or between parasite stages) will be one of the important challenges of coming years.
We were unable to obtain a useful estimate of the likely efficacy of the DNA ME-TRAP/MVA ME-TRAP vaccination regime against clinical disease. Even for an adult population, the incidence of clinical disease was lower than expected. Sulphadoxine/pyrimethamine was administered 4 wk before the start of surveillance in this study and in an RTS,S field efficacy study [30
]. There is some evidence that pretreatment with this antimalarial reduces the incidence of clinical malaria for longer than 4 wk [35
]. However, there was also less clinical disease than in recent years in paediatric cohorts recruited for other studies in 2002 at the study site, probably for climatic reasons.
This study highlights North Bank Division in Gambia as an excellent malaria vaccine field trial site both for adults and, by extrapolation, for children. In a low-transmission year, cumulative incidence overall in men aged 15–45 y was 72% over 11 wk, which was higher than expected. Also, compliance was good despite a demanding study design, and migration from the study area was acceptably low.
This paper adds to the body of data detailing the very gradual acquisition of anti-infection immunity in adults resident in sub-Saharan Africa [30
]. While substantial immunity to severe malaria is acquired after only a few infections and anti-disease immunity is acquired in childhood, we saw statistically significant decreases in incidence of infection with increasing age in the 15–45 age range (). The protection against infection for those with Fula ethnicity observed in this trial is consistent with a report from Burkina Faso [37
]. The Fulani mostly reside in distinct villages in this part of Gambia.
Immunological analysis of the high level of protection inducible by immunisation of humans and animals with irradiated sporozoites has encouraged attempts to generate protective immunity by subunit vaccines that induce strong cellular immune responses. To date the induction of high-level protective T cell responses against malaria and some other infectious pathogens has generally required two-component prime-boost vaccination approaches [38
]. We report the first field efficacy trial of a subunit vaccine designed to induce protective immunity through effector T cell rather than antibody induction. Effector T cell induction 50-fold greater than that generated by natural malaria infection is now possible through DNA-based heterologous prime-boost vaccination of humans. However, further development of T cell–inducing vaccines will be required to evaluate the effects of altering the characteristics, target antigen specificities, and durability of the induced T cells in order to generate higher levels of protective immunity against malaria.
Malaria kills 1–2 million people a year, mostly children under the age of five who live in sub-Saharan Africa. Scientists are trying to develop cheap, safe, and effective vaccines that could be given to people living in regions where malaria is very common to prevent them from developing the disease.
What Did the Researchers Find?
The researchers enrolled 372 Gambian men aged 15–45 years into the study. They injected half the men with two malaria vaccines, one after the other, and half the men with a rabies vaccine that does not protect against malaria (this vaccine was given so that “control” participants would have some benefit from being in the trial) just before the rainy season, when malaria is especially prevalent. The scientists took blood smears from the men once a week and checked to see if they had been infected with the parasite that causes malaria. They found that the men who had been vaccinated became infected just as quickly as those who had not. Although the two malaria vaccines in concert did not work, neither did they cause any serious side effects. The men given the malaria vaccines did produce an immune response to the vaccines, though not one that was clinically useful.
What Does This Mean for Patients?
It looks as though the combination of these two vaccines is not effective at preventing infection with Plasmodium falciparum, the parasite that causes malaria. However, there are other vaccines in development that have not been tested yet.