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Cross-strain sterile, durable protection against malaria Plasmodium falciparum using chemoattenuated whole sporozoite vaccines

July 2, 2021 - 11:41 -- Sanaria Inc.

Sanaria® PfSPZ-CVac vaccine protected 100% of six subjects against a genetically distant variant parasite strain for 3 months, the first time that such complete protection has ever been achieved for such a long period.  Results set the scene for development of a traveler’s vaccine, seasonal malaria vaccinations and genetically attenuated parasites that do not fully develop in the liver through to early blood stage.

This week, the most recent findings from Sanaria Inc. and our colleagues in the Laboratory of Malaria Immunology and Vaccinology at the National Institutes of Health (NIH) were published in Nature [1], demonstrating unprecedented sterile protective cross-strain immunity at 3 months after the last dose of vaccine using Sanaria’s PfSPZ-CVac (Chemoprophylaxis Vaccine).

Sanaria® PfSPZ-CVac uses live, infectious Plasmodium falciparum sporozoites (PfSPZ) administered alongside an antimalarial drug, in this case choloroquine (CQ) or pyrimethamine (PR), to kill early blood stage (CQ) or liver stage (PYR) parasites before a clinical infection can develop.

Sanaria has also pioneered the use of infectious PfSPZ, known as PfSPZ Challenge, to test vaccine efficacy and better understand natural immunity, using controlled human malaria infection (CHMI). In this study, CHMI was done using PfSPZ Challenge (7G8), the parasites of which are genetically far removed from the PfNF54 strain that comprises all of Sanaria’s whole sporozoite vaccines, including PfSPZ-CVac and also more genetically distant from the vaccine parasites than all African isolates of Pf examined to date [2]. Testing efficacy with this divergent parasite is a rigorous test and requires only small numbers of trial participants since 100% of unvaccinated subjects develop malaria; in this trial all 12 controls became infected.

What makes these results worthy of publication in Nature? PfSPZ-CVac (CQ) was safe and protected 100% of six subjects against Pf7G8 parasites at 3 months after the last vaccine dose. This is the first time that sterile protection of all vaccinated subjects against a variant, genetically distant malaria parasite has ever been achieved after such a long period following vaccine administration. This builds upon the 77% protective efficacy against CHMI with Pf7G8 at 3 months obtained with that a lower dose of PfSPZ (55% of the dose in this study) administered over a shorter period (4 weeks vs 8 weeks) done in collaboration with colleagues at the University of Tübingen [3].

The Nature paper also included results of a second study group using PfSPZ-CVac (PYR), a drug used for seasonal malaria prevention in African preschool children. This vaccine was well tolerated and protected 82% of the 17 subjects from the same Brazilian variant parasite or the African vaccine parasites, also at three months after the last dose. Since pyrimethamine killed the parasites in the liver, this portion of the trial showed that the potent vaccine efficacy of PfSPZ-CVac does not rely on induction of immunity by asexual erythrocytic stage parasites.

Together these data show again that PfSPZ-based vaccines confer sterile protective immunity against genetically distant parasites. The length of protection tested is already sufficient for application as a vaccine for travelers to malaria endemic areas. However, the results pave the way for a robust seasonal malaria control using drugs that are already deployed in the African setting. Indeed, one of the early clinical trials using mosquito bite immunization with CQ called CPS [4] showed that protection against infection, rather than disease, could last for up to 28 months in some volunteers [5], clearly demonstrating the huge potential of this approach.

But these results also offer exciting long-term possibilities. As noted in the commentary by Nana Minkah and Stefan Kappe [6] in the same issue of Nature, these results reinforce the importance of developing whole parasite pre-erythrocytic vaccines against malaria, the only approach to repeatedly show sterile protection against infection. As these authors state, knocking out (removing) parasite genes otherwise required for completing liver stage development causes the parasites to halt their development late in the liver stages, potentially providing equivalent protection without the need for drug cover.

Sanaria’s vaccine development program is designed to produce safe, cost-effective vaccines that provide high-level protection against malaria parasite infections that cause more than 400,000 deaths annually, primarily in Africa. With this goal in mind, Sanaria and our partners in the International PfSPZ Consortium have pursued a step-by-step approach to maintaining safety while increasing efficacy against variant parasites and naturally genetically heterogeneous malaria, prolonging the durability of efficacy, and decreasing the required vaccine dosage. This study reports huge progress in all four areas.

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[1] Mwakingwe-Omari et al. 2021. Two chemoattenuated PfSPZ malaria vaccines induce sterile hepatic immunity.  Nature doi.org/10.1038/s41586-021-03684-z
[2] Moser et al. 2020. Strains used in whole organism Plasmodium falciparum vaccine trials differ in genome structure, sequence, and immunogenic potential. Genome Med 12, 6 (2020)
[3] Mordmüller et al. 2017. Sterile protection against human malaria by chemoattenuated PfSPZ vaccine. Nature 542:445-449
[4] Roestenberg et al. 2009. Protection against a Malaria Challenge by Sporozoite Inoculation. N Engl J Med 361:468-477
[5] Roestenberg et al. 2011. Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study. Lancet 377:1770-1776
[6] Minkah NK, Kappe SHI. 2021. Malaria vaccine gets a parasite boost in the liver. Nature doi.org/10.1038/d41586-021-01720-6