Experimental malaria vaccine shows 55% efficacy in small trial

This week Nature Medicine published results from small trial involving controlled human malaria infection (CHMI) and experimental malaria vaccine developed by Sanaria (Sanaria Inc., Rockville, Maryland, USA). This vaccine based on attenuated Plasmodium falciparum sporozoite (abbreviated as PfSPZ vaccine) showed 55% efficacy at 1 year post-immunization.

Currently, only malaria vaccine available on market, RTS,S, has efficacy of ~ 22%. In this new study, scientists tested different dosages and routes of immunization for new PfSPZ vaccine as follows:

The results of the controlled human malaria infection are shown below. Here, healthy malaria-naive volunteers were first vaccinated and then received malaria infection from actual mosquitoes bites that carry malaria clone 3D7. The best outcomes were achieved with groups 4 and 5 (i.v. administration, 4 doses of 2.7 × 10⁵ PfSPZ).

Next step was to understand immunological correlates of protection. However, this task was quite challenging, as it turned out. All vaccination protocols, with the exception of i.m. immunization, induced anti-malaria Ab or T cell responses. However, when vaccine trial participants were divided based on blood parasitemia following malaria challenge, it was observed that participants without parasitemia developed higher levels of anti-malaria serum Abs.

At the cellular level, however, the only marker that correlated with vaccine efficacy was frequency of unstimulated Vγ9+Vδ2+ γδ T cells which comprises ~75% of γδ T cells in blood. Actually, the frequency of Vγ9+Vδ2+ γδ T cells in pre-vaccinated individuals was the only marker that correlated with vaccine efficacy in challenge model.

In summary, this study showed that there is still room to improve malaria vaccine. Vaccine efficacy of 55% in 1-year followup is a significant progress when considering that In 2015 there were an estimated 214 million clinical cases of malaria in the world. Another outcome of this study is that fact that it is quite hard to find or define immune correlates of protection and this is especially true for parasitic infection such as malaria or dengue.

David Usharauli

Sweet rejection: sugar-coated malaria parasite

Life is a competition, even for a parasite like a malaria. To infect the host the parasite needs to overcome not just host's defense system but to out-compete the local resident micro-flora as well. 

This new paper in Cell is a thorough research about the initial events of of malaria infection and the role of sugar molecules, called glycans, in the host defense against malaria.

It is well-known that hosts and their parasites may share molecular signature. Blood types, ABO system is one such example. Burnet's clonal selection theory predicts that any such similarity between host-pathogen prevents the host to mount an efficient immune response against shared antigens. As a consequence, based on pathogen burden and evolutionary pressure, the hosts started to loose the capacity to express such shared molecules.

It appears that at some point in their evolution human ancestors lost the capacity to make one type of sugar, alpha-gal, expressed by malaria. This change conferred an improved capacity to defend against malaria. 

This papers shows how exactly such modification provided protection. It turns out to be dependent of natural immunization conferred by gut resident microbes expressing the same exact sugars.

Analysis of serum samples across different age group from children in Mali (malaria endemic region), the authors noticed a gradual increase in anti-alpha-gal IgM level over time. Interestingly, 6-months parasite free condition correlated with higher level of anti-alpha-gal IgM in the serum.

To study this observation in laboratory setting, the authors used mice deficient in the capacity to make alpha-gal (alpha-gal KO). This "human-like" mice can produce anti-alpha-gal antibodies upon colonization with alpha-gal-positive E.coli O86:B7, but not alpha-gal-negative E.coli K12 strain. 

The authors showed that colonization of alpha-gal KO mice with alpha-gal-positive E.coli O86:B7 provided a protection against malaria transmission.

This protection after gut flora colonization was conferred by soluble germ-line, non-mutated IgM.

Immunization of alpha-gal KO mice with  (a) alpha-gal conjugated to BSA (protein carrier) or (b) rabbit RBC (naturally expressing high levels of alpha-gal) conferred protection against malaria transmission.

Deep analyses of mechanism of protection after immunization revealed it was dependent on T cell help and on both IgM and IgG (of note, immunization with rabbit RBC conferred protection even in IgM-deficient mice, unlike protection conferred after colonization with alpha-gal expressing E.coli O86:B7).

The protection could be conferred by passive transfer with IgM, IgG3 and IgG2b, but not IgG1 and IgG2a.

In summary, this study provides evidence how gut flora affects host's defense against parasites by a way of natural immunization. Of course, it is remains to be determined whether immunization against alpha-gal will protect humans as well as it does for "human-like" mice.

David Usharauli