WHAT'S NEW THIS SUNDAY: MALARIA VACCINE TRIALS

Friday, 9th of November 2012

MALARIA VACCINE TRIALS — BEYOND EFFICACY END POINTS

Below, editorial from the New England Journal of Medicine, commenting on Phase 3 results from Africa.

See also item in New York Times, http://www.nytimes.com/2012/11/10/health/malaria-vaccine-candidate-produces-disappointing-results-in-clinical-trial.html?gwh=680E1945DF185373562B58D0C91EB5B1

Editorial, NEJM

Johanna P. Daily, M.D.

November 9, 2012

DOI: 10.1056/NEJM

This editorial refers to original Phase 3 vaccine trials reported in the same number of the New England Journal of Medicine, best viewed at

http://www.nejm.org/doi/full/10.1056/NEJMoa1208394?query=featured_home

Plasmodium falciparum infection, malaria, continues to cause more than 1 million childhood deaths each year.1 In addition, millions of nonlethal infections affect communities on an economic basis and inhibit children from reaching their full developmental potential.2 The creation of an effective vaccine has been a long-sought, elusive goal.

The first results of the phase 3 trial of the candidate malaria vaccine RTS,S/AS01, which is being conducted in seven African countries, were reported for children 5 to 17 months of age at enrollment, with a vaccine efficacy of 56% against all clinical malaria infections and 47% against severe malaria during a 12-month follow-up period.3 This vaccine targets the circumsporozoite protein, which is responsible for liver invasion — a critical first step to establish infection in the human host.4

The RTS,S Clinical Trials Partnership now reports in the Journal 5 the results of the same study for children 6 to 12 weeks of age. RTS,S/AS01 or a comparator vaccine was administered to 6537 infants. Vaccine efficacy against clinical malaria was 31% in the per-protocol population, and efficacy against severe malaria was 26% in the intention-to-treat population. For both end points, the efficacy was much lower than that observed among older children.

Why has the development of a malaria vaccine been so challenging, and what are the implications of a lower efficacy among infants? Vaccine developers are faced with an organism that resides in the peripheral-blood compartment and that boldly circulates alongside immune cells and proteins to facilitate further transmission. The success of this pathogen is related to prolonged coevolution with humans, allowing the development of cunning biologic strategies to resist immune-system clearance.

Another challenge to vaccine development is that sterilizing immunity does not occur naturally. Infected children and previously unexposed travelers have a wide spectrum of disease and risk of death. In contrast, residents of high-transmission areas acquire partial protection, as studied by Robert Koch as early as 1900, which results in a lower prevalence of severe malaria, lower parasite burdens, and less frequent clinical illness. What mediates this acquired partial protection? Which adaptive responses are central to this observed state of relative protection among those living in endemic areas? Do these immunologic correlates of protection after repeated natural infection have relevance to vaccine development? Mechanisms of vaccine protection may be distinct from those of natural immunity. However, the identification of an effective host response can inform the engineering of modified vaccines with specific immune-modulatory properties.6

Despite these challenges, the achievement of a vaccine efficacy against clinical malaria of 56% among children 5 to 17 months of age was remarkable. The current study shows a much lower efficacy for both end points among children 6 to 12 weeks of age. As noted by the authors, there are several potential reasons for the lower efficacy, including immunologic immaturity in neonates, interference from maternal antibodies, and less prior exposure to malaria (perhaps this vaccine functions as a “booster” and requires immunologic priming). Further analyses from this study, such as assessments of vaccine efficacy according to malaria-transmission intensity and assessments of the presence of maternally derived infant immunity at the initiation of the vaccine series, should enlighten us about potential mechanisms.

Another fundamental question is why protection was achieved in some infants and not in others. A thorough analysis should be undertaken to determine which vaccine-elicited immune responses might have afforded protection, as has been conducted in the pursuit of a vaccine against the human immunodeficiency virus.7 Although the authors measured antibodies to the circumsporozoite vaccine antigen as a marker of vaccine response, measures of immune response should be greatly expanded upon, as has been done with other vaccines. For example, a comprehensive analysis of antibodies, cytokines, immune cells, and whole-genome transcription after yellow-fever vaccination led to the identification of key host responses associated with an effective response.8 Recent studies leveraging comprehensive immune analysis to inform disease and immune-response models in malaria could also inform the development of malaria vaccines.9

The results of this trial suggest that this candidate malaria vaccine is not ready to become part of the routine panel of infant immunizations. However, this trial did show protection in a subset of children and thus should be used as an opportunity to enlighten researchers regarding the host responses that correlate with vaccine protection. There are many vaccine candidates in the pipeline that use alternative parasite targets and vaccination strategies.10 Whether leaders in malaria-vaccine development will be able to support the costs needed to integrate sophisticated host-response studies or other value-added studies into these future vaccine trials remains to be seen. The results of this immunization trial suggest that a malaria vaccine is possible, but a more detailed understanding of effective host responses will be necessary to achieve this goal and avert the illnesses and deaths associated with this devastating infection for millions of children.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

This article was published on November 9, 2012, at NEJM.org.

Source Information

From the Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, NY.

References

1 Murray CJ, Rosenfeld LC, Lim SS, et al. Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet 2012;379:413-431
CrossRef | Web of Science

2 Kihara M, Carter JA, Newton CR. The effect of Plasmodium falciparum on cognition: a systematic review. Trop Med Int Health 2006;11:386-397
CrossRef | Web of Science

3 Agnandji ST, Lell B, Soulanoudjingar SS, et al. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N Engl J Med 2011;365:1863-1875
Full Text | Web of Science

4 Coppi A, Natarajan R, Pradel G, et al. The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host. J Exp Med 2011;208:341-356
CrossRef | Web of Science

5 The RTS,S Clinical Trials Partnership. A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N Engl J Med 2012. DOI: 10.1056/NEJMoa1208394.

6 Nambiar JK, Ryan AA, Kong CU, Britton WJ, Triccas JA. Modulation of pulmonary DC function by vaccine-encoded GM-CSF enhances protective immunity against Mycobacterium tuberculosis infection. Eur J Immunol 2010;40:153-161
CrossRef | Web of Science

7 Haynes BF, Gilbert PB, McElrath MJ, et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med 2012;366:1275-1286
Full Text | Web of Science | Medline

8 Querec TD, Akondy RS, Lee EK, et al. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nat Immunol 2009;10:116-125
CrossRef | Web of Science

9 Tran TM, Samal B, Kirkness E, Crompton PD. Systems immunology of human malaria. Trends Parasitol 2012;28:248-257
CrossRef | Web of Science

10 Initiative for Vaccine Research. Malaria vaccine “Rainbow Tables.” Geneva: World Health Organization, 2012 (http://www.who.int/vaccine_research/links/Rainbow/en/index.html).