The NY Times recently ran an article on a World War 2 group “officially called Malaria Control Unit Cactus, but unofficially known as the Skeeter Beaters”. The small unit consisted of mostly US Navy Corpsmen volunteers and their exploits were relived in a 2002 book by Dennis Cline, “Skeeter Beaters: Memories of the South Pacific, 1941-1945.” But Mr Cline didn’t stop with the book, he is raising money to fight malaria in the unit’s honor and his foundation hopes to send 20,000 insecticde treated nets to the Solomon Islands.

You can support their efforts by either donating directly for the purchase of nets or buying clothing with their terrific logo here.

1. “Flying syringes” - the efforts of Dr Matsuoka from Jichi Medical University in Japan to produce a transgenic mosquito, as a flying syringe, to deliver protective vaccine via saliva.
2. “Microwave therapies” - Dr Spadafora from the Institute for Advanced Scientific Research in Panama wishes to use microwave frequency as a treatment for malaria

Presently, in vivo efficacy trials are the gold standard for anti-malarial drug resistance monitoring. In vivo trials involve treating a cohort of malaria patients and subsequently checking their blood at regular intervals to detect parasites. Thus, in vivo studies are not direct measures of parasite resistance per se - as other factors such as host immunity and pharmacokinetics play a role, but the outcome (treatment failure) is directly relevant to programs. However, implementing in vivo studies presents several challenges in endemic settings including cost, well-trained staff, lengthy periods of patient follow-up (28 to 63 days), and the need to distinguish treatment failures as recrudescences or reinfections. Since most malaria control programs have limited resources, only a few in vivo trials can be conducted each year. An alternate method to extend the surveillance of antimalarial efficacy is to measure molecular markers of drug resistance.

We employed a molecular surveillance system in Cambodia (Emerging Infectious Diseases Journal - open access) to help detect ACT resistance. This new tool does not replace the standard in vivo trial but rather enables a more efficient use of existing resources. Using this system, a high level of artesunate-mefloquine failures (which were previously believed to be confined to the Thai border) was discovered in the center of the country. Here’s a quick summary of the benefits:

Monitoring changes in antimalarial efficacies is essential for control programs in an era of multi-drug resistance. However, such studies are resource intensive. In Cambodia, for example, the National Malaria Control Program can manage to conduct in vivo studies at only 2-3 sites per year because of limited funds and trained staff. Molecular markers can help target in vivo studies to where they are needed the most. Molecular surveillance is high-throughput and can be performed in a central laboratory on dried blood spots, which are easily collected in the field. Expanded molecular surveillance could also accurately help map anti-malarial resistance and enable sub-national treatment policies in countries with marked geographic variation in drug susceptibility.

What excites me about this work is the translation of molecular knowledge into a monitoring tool for informing policy and improving malaria control operations. I think the last two sentences of the paper say it all:

pfmdr1 assays are now routinely performed in Cambodia by National Malaria Control Program staff. National and regional molecular surveillance by malaria-endemic countries is a real possibility.

Donors have committed an initial $3 billion towards the actions outlined in the plan. The bulk of the funds were pledged by the World Bank ($1.1 billion) and the Global Fund ($1.6 billion). I believe the total amount includes  $168.7 million from the Gates foundation to fund work on new malaria vaccines. The total cost of the global strategy is estimated to average US$ 5.9 billion per year from 2011 to 2020.

A lesser known fact regarding the Global Malaria Action Plan is that the private firm Boston Consulting Group was brought in to do the bulk of the work. There’s nothing wrong with their involvement - in fact I would credit RBM for allocating priority to the plan and bringing in outside help to develop it rapidly and effectively. However, it begets the question of why an organization housed within the foremost body in international health does not have the internal capacity to develop a global strategy plan?

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.

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.

Lines et al. describe the potential risks of promoting elimination - inequitable distribution of resources, resistance to drugs and insecticides, and management challenges present when deploying multiple interventions. In a rapid response Gosling and Chandramohan point out the risks attributed to elimination programs are not unique and apply to sustained control efforts as well (including resurgence and epidemics). While one could debate the magnitude of those risks in each type of program, Gosling and Chandramohan are essentially right. I felt the article could have been stronger if the authors had instead elaborated on some of their summary points, namely:

Nevertheless, there are important practical differences between elimination and control, notably in the relative priority given to high and low burden target areas, the choice and timing of interventions, and the need for integration with general health services.

In high burden areas, where elimination is currently not feasible, health impact will be maximized by aiming to develop universal coverage in the context of health systems.

The impact that a re-orientation towards elimination would have on generalized health systems is an important concern. For areas without an effective health system it is a moot point, but in many countries components of malaria control are effectively (and inexpensively) delivered through primary care. Finally, the biggest concern may be a question of managing expectations which was not fully discussed. Expectations related to the concept of elimination among donors, policy makers, health workers, and communities are bound to be much higher than what is realistic and a nuanced explanation of a long term vision is unlikely to temper those beliefs. Vision is a beautiful thing but we need proper communication to maintain trust, and proper execution to really benefit lives.

New interventions designed to target human and vector populations that are hardest to reach

New interventions that will be valued and used by individuals and communities even after malaria rates fall and the perceived threat of the disease is low

New tools and technologies for monitoring and surveillance of the pathogen, including methods to detect latent and subclinical infection in both human and non-human reservoirs and vectors

New tools and approaches for reducing malaria transmission, especially from low levels to zero

New strategies to apply interventions to populations, such as those considering the underlying heterogeneity of human, mosquito, and parasite populations in space and time

Political and financial commitments will be first and foremost towards embarking on any major effort. Obtaining these (with some level of confidence) is a perilous proposition in itself but will not be sufficient for many parts of the world which have high vectorial capacity (in plain English - really efficient mosquitoes). Data from a number of long term field trials and mathematical models along indicate our inability to eliminate parasite reservoirs in these areas even with near universal application of current interventions. Whether eradication should be on the table is another question altogether, but if Gates is serious about eradicating malaria then finding new tools is a solid move.

Excerpts:

Multidrug-resistant malaria, including artemisinin resistance at the border of Cambodia and Thailand, threatens to jeopardize the provision of effective antimalarial treatment worldwide…

A theme issue of the Bulletin will provide a forum for sharing the region’s successes, and its future opportunities in disease control and research. The issue aims to foster greater international collaboration and partnership. Since the region has such a high communicable disease burden and risk, greater investment and collaboration will benefit not only the communities it serves but the entire world.

It’s not about the importance of SE Asia vs Africa or any other region - that would be silly. We take a brief snapshot of accomplishments, current challenges, and recent innovations in SE Asia to highlight the value of investment in control, elimination, and research. All in all, its an impressive rate of return. The practical point of the editorial is to provide the rationale for a full region-specific Bulletin issue. It’s a call for papers and the resultant issue should be a great forum for anyone interested in reaching a broad audience.