Monday, August 19, 2013

Attenuated Sporozoites in Blood is Protective?


      Just a few blog posts ago, I had posted about Malaria. I ventured into various possible methods that can be looked into to control the Plasmodium infection. In the post, I mentioned of a vaccine candidate RTS,S/AS01 vaccine (Reference). I also expressed issues of very low efficacy as a concern. But a recent paper published in Science, has claimed a 100% protection. Which means I really need to talk about it. Before you go through this, I would suggest that you have a background reading from my previous post.

Photo 1: Plasmodium malariae schizont
   Vaccination has been a fantastic tool of medicine (in situations where it can be applied). The lack of an excellent vaccine against the Plasmodium species, especially P vivax and P falciparum, is reflected in the global burden of the disease. The disease usually seen in tropics has mounted a great deal of science and challenge. The best known of the malaria vaccines is RTS,S/AS01 vaccine, pursued by GSK targeting the CSP (Circumsporozoite protein) showed a great promise. But eventually in follow up studies it failed to demonstrate expected levels of protection (which was less than 40%). Though the study hasn't concluded yet, and data collection is still on process the vaccine is considered as pretty much a failure by many.

     This stages a debate as to what can be the reason for vaccine failure with such good potential. One of the explanation was that probably Plasmodium never produces a long lasting immunity (there are other examples of similar candidates), and hence the RTS,S/AS01 (Mosquirix) still be considered. Perhaps we should think otherwise.

     This study is a phase 1clinical trial (Safety study), of Sanaria ® PfSPZ Vaccine, primarily funded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) with additional support from the Naval Medical Research Center and Sanaria. The vaccine material is sporozoite recovered from the salivary glands of mosquito that has been purified, cryopreserved. They were radio treated and attenuated. These attenuated sporozoite now referred as PfSPZ, invade hepatoctyes and expresses new proteins, but cannot replicate. Studies earlier showed that it is safe and well-tolerated when administered ID or SC to volunteers, but sub-optimally immunogenic. So this new approach used intravenous route.

Photo 2: Plasmodium Sporozoite.
   The basis of this study has roots in some older studies. Inactivated sporozoites had been shown to be promising. It was later shown that CSP was immunologically important and clinical trials were conducted with a sporozoite vaccine called SPf66. Due to its low efficacy, it wasn't further pursued. A significant leap was made by Mueller AK, by identifying UIS3 (upregulated in infective sporozoites gene 3) gene, which when deleted showed inability to replicate in hepatocytes. Immunization with UIS3-deficient sporozoites showed complete protection against infectious sporozoite challenge in a rodent malaria model.

    So what does this study offer? Give this a thought. You have to vaccinate millions of people around the tropics by giving an intravenous (i.v) dose of vaccine. This is a very unusual way of delivering vaccine. Moreover mass immunization with this method requires a good technical support. The point of this vaccine is inducing immunity at pre ertythrocytic stage. This study is a proof of concept study, that malaria can be immunized against. This provides us with a model to establish co-ordinates of immunity from which we can further develop. Stefan Kappe, a malaria researcher says "The trial results constitute the most important advance in malaria vaccine development since the first demonstration of protection with radiation attenuated sporozoite immunization by mosquito bite in the 70s." Source

   This study involved 60 patients. Of the participants who received the mosquito challenge, 11 of 12 who were not vaccinated became infected, 16 of 17 in the lower vaccine dose groups became infected, and only 3 of 15 subjects in the high-dose vaccine groups became infected. None of the six subjects that received five doses were infected. The maximum dose that was given was 135,000 sporozoites. Please note 100% efficacy is with 5 iv doses.

    For me, the take home message is obvious. When Sporozoite is given through natural route (intravenous) of infection, with high load the immune system responds well. Probably we were looking in wrong direction. This vaccine will advance our knowledge on Plasmodium control, but am a bit skeptical. We had similar results with CSP and Phase I is just the start of it, not the final verdict. Moreover 5 heavy doses intravenous is a bit asking for too much especially in population of underdeveloped countries. Always a scope for improvement.
Seder etal (2013). Protection Against Malaria by Intravenous Immunization with a Nonreplicating Sporozoite Vaccine. Science (New York, N.Y.) PMID: 23929949

Garcia JE, Puentes A, & Patarroyo ME (2006). Developmental biology of sporozoite-host interactions in Plasmodium falciparum malaria: implications for vaccine design. Clinical microbiology reviews, 19 (4), 686-707 PMID: 17041140

Stephen L Hoffman. Adaptive clinical trials of three PfSPZ products for development of a whole sporozoite vaccine that prevents Plasmodium falciparum infection, disease and transmission. Malaria Journal 2012, 11(Suppl 1): O48. doi:10.1186/1475-2875-11-S1-O48.

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