Resurrecting the past to create a new malaria vaccine

I should begin with a disclaimer – I’m not a malaria vaccine researcher. The idea I’m proposing may be a dead end, or possess some fatal flow unknown to me. Still, from what I do know, it seems to make a lot of sense. I came to this idea after looking into older research regarding the epidemiology of gametocytes (the sexual stage of malaria parasites which is transmitted to mosquitoes). Some of the jargon below is a bit technical, but the basic idea is to use whole parasite stages to induce transmission blocking immunity (would not protect the individual but prevents the subsequent transmission of the infection). I have neither the expertise in this area nor the time to pursue the research – but here it is out in the open so someone might take it up and run with it:

An effective malaria vaccine remains elusive after decades of research. Current vaccine candidates demonstrate either limited protection and/or limited duration of protection. The contemporary paradigm of vaccine development using subunits has proven largely unsuccessful and points to the need for a new strategy – or perhaps an old one. “Crude vaccines” using whole cell approaches might be necessary to provide sufficient and robust protection against the parasite. In fact, the candidate vaccine with the best efficacy (albeit in a small sample) is the irradiated sporozoite vaccine being developed by Sanaria, Inc. However, this approach is expensive and will likely only provide a limited duration of protection. Another possible whole cell approach is the use of killed gametes. This idea has several merits. First, gametes are not part of the human stage of the parasite life cycle and therefore their antigens are under limited host selection pressure. Second, a whole cell vaccine induces broader immunity against multiple antigens making immune evasion by the parasite less likely. Third, gametocytes can be cultured in vitro which reduces the cost and complexity of creating vaccine relative to harvesting sporozoites from mosquitoes. Finally, several studies from the late 1970s showed near 100% transmission blocking protection in several animal models.

Species Animal model TB Efficacy (%) Dose (weeks given) Year Ref
P.gallinaceum Chicken 100 10^5 (5) 1976 1
99.9 10^5 (4)
96.2 10^5 (3)
P.gallinaceum Chicken 100 2.7^5 (3) 1976 2
P.knowlesi Rhesus monkey 100 10^7 + FCA (1) 1978 3
99.9 10^6 + FCA (2)
96.3 10^5 + FCA (1)
P.yoelli Mouse 100 2^8 + FCA (3) 1979 4

Why was such a promising approach abandoned?
A whole gamete vaccine was not furthered developed in humans because gametocyte yields from culture were low and the process was labor intensive (making obtaining the necessary doses very expensive) – if this could be overcome it would be a different matter. Also, safety concerns existed as parasites were grown in human blood. With the advent of powerful new molecular biology techniques, it was thought a subunit approach using gamete surface antigens would overcome the aforementioned challenges. Unfortunately, the subunit results have not proved as efficacious as whole gamete preparations.

Can we economically and safely produce a whole gamete vaccine?
Safety remains a challenge but if Sanaria, Inc can use blood fed mosquitoes to produce a live vaccine under GMP/FDA approval, then this obstacle may be overcome. In 2007, Fivelman et al. (5) reported an improved method for producing P.falciparum gametocytes in vitro through which one can reliably obtain 50 million stage V gametocytes from 100mL of culture. How many doses could this provide? Well, a key unknown exists: how many gametes are needed for an inoculating dose in humans? In any case this can be determined. The production process is where innovation needs to happen. An industrial culture system, finding the biochemical “signal” to induce gametocytogenesis, etc could be possibilities. To paraphrase a communication I had with one of the original researchers – the gametes worked as transmission blocking immunogens, anyone who could solve the problem of gamete mass production would have a great resource on their hands. In the end, a broad portfolio of vaccine development approaches will provide the best chance for producing a deployable vaccine. A whole gamete vaccine should be considered one key approach.

References
1. Gwadz, RW. 1976. Malaria: Successful immunization against the sexual stages of Plasmodium gallinaceum. Science 193, 1150-1151.
2. Carter, R., Chen, DH. 1976. Malaria transmission blocked by immunization with gametes of the malaria parasite. Nature, 263, 57-60.
3. Gwadz RW, Green I. Malaria immunization in Rhesus monkeys. A vaccine effective against both the sexual and asexual stages of Plasmodium knowlesi. J Exp Med. 1978 Nov 1; 148(5):1311-23.
4. Mendis et al. Immunization against gametes and asexual stages of a rodent malaria parasite. Nature. Vol 277, Feb 1979, 389-391.
5. Quivelman et al. Improved synchronous production of Plasmodium falciparum gametocytes in vitro. Molecular and Biochemical Parasitology. 154 (2007) 119–123
6. Malaria transmission blocking vaccines: an ideal public good. UNDP/World Bank/WHO/TDR. 2000.

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