Fighting the scourges of humanity

The past week has seen some interesting news on efforts to combat three diseases that blight the lives of millions in the world today.

The most exciting news was that in two studies (1,2) published this week in the New England Journal of Medicine the malaria vaccine RTS,S passed a major milestone in its development by showing that it could safely protect infants against malaria infection.  These results pave the way for larger phase III studies, and if these are successful RTS/S could soon be an important component of ongoing anti-malaria strategies alongside insecticide-treated bed nets and recently developed artemisinin-based combination drugs.

The clinical development of RTS,S has been a long process that began as a collaboration between the Walter Reed Army Institute of Research (WRAIR)and GlaxoSmithKlein in the late 1980’s. Two key discoveries guiding the development of RTS,S were the finding in mice (3) that in order to immunize against malaria infection it is necessary to stimulate a cell-mediated immune response in addition to an antibody-mediated response, and the simultaneous discovery by scientists at WRAIR that incorporating a hepatitis B surface antigen into the malaria vaccine construct improved its ability to induce an immune response in mice and rabbits (4).

While the news of RTS,s good performance in clinical trials is to be welcomed it is worth noting that it does not protect everyone, with the best protection rates being in the 60% range, so ideally it should be combined with other vaccines that target different stages of the malaria parasite’s life cycle.  Research into such vaccines being performed at several institutes worldwide, including  the  Jenner Institute in Oxford whose work I discussed earlier this year.

Another medical research story that has been widely reported is a study indicating possible role for the cold sore virus HSV1 in Alzheimer’s disease. The interesting thing here is that while there has been a lot of research done on the role of aggregation of beta-amyloid  into extra cellular plaques and tau proteins into intracellular tangles, there have been few clues as to what causes these proteins to aggregate in the first place.  This work suggests that HSV1 infection may trigger the formation of beta-amyloid plaques.  The research published this week involved analyzing the brains of Alzheimer’s patients and non-alzheimer’s controls, but as the authors point out in the paper the presence of HSV1 in amyloid plaques is not in itself proof of a role for HSV1 in the plaque formation, so they refer readers to an earlier paper (5) where they demonstrated that  mice infected with HSV1 developed beta-amyloid plaques in their brains, and in vitro studies that show that HSV1 can increase the activity of enzymes responsible for producing beta-amyloid. The observation that there is a causal relationship between HSV1 infection and the development of beta-amyloid plaques spurred Professor Itzhaki and her colleagues at the University of Manchester to examine human brains for signs of an association between HSV1 infection and Alzheimer’s disease.  This work is at an early stage, and while HSV1 infection may be a trigger it is likely that other factors such as an individuals genetic makeup are also important in the development of Alzheimer’s. If the involvement of HSV1 is supported by further studies anti-viral drugs may be used to help slow the progression of the disease, and perhaps even stop it entirely if administered early enough.

Finally scientists at the Yerkes National Primate Research Center in Atlanta have shown that a novel way of fighting viral infection can stave off death from AIDS in SIV infected monkeys (6).  This line of research was kicked off  a decade ago by work undertaken in mice infected with the rodent-borne lymphocytic choriomeningitis virus showing that exhaustion of a population of immune cells termed CD8+ T-cells which target viruses led to loss of the ability to control infection. An increase in the amount of a receptor protein called PD-1 on CD8+ T-cells was associated with exhaustion and that their anti-viral activity was restored by treating the mice with antibodies that blocked PD-1.  Subsequently researchers found that in SIV infected monkeys and HIV patients increased PD-1 is also associated with CD8+ T-cell exhaustion and progression to AIDS, but until now it has not been clear if blocking PD-1 will help prevent progression of AIDS.  So far the results from Yerkes are encouraging, and further testing is now underway to determine whether anti-PD-1 treatment remains effective over longer periods of time, and whether it can also be used to treat other chronic viral infections such as hepatitis C.

All in all an interesting week!

Paul Browne
1) Bejon P. et al. “Efficacy of RTS,S/AS01E Vaccine against Malaria in Children 5 to 17 Months of Age” NEJM Vol.359, pages 2521-2532 (2008) DOI:10.1056/NEJMoa0807381

2) Abdulla S. et al. “Safety and Immunogenicity of RTS,S/AS02D Malaria Vaccine in Infants”  NEJM Vol. 359, pages 2533-2544 (2008) DOI:10.1056/NEJMoa0807773  3) Schofield L. “Gamma interferon, CD8+ T cells and antibodies required for immunity to malaria sporozoites” Nature Vol. 330(6149), pages 664-666 (1987) DOI:10.1038/330664a0

4) Rutgers T. et al. “Hepatitis B Surface Antigen as Carrier Matrix for the Repetitive Epitope of the Circumsporozoite Protein of Plasmodium Falciparum” Biotechnology  Volume 6, pages 1065 – 1070 (1988) DOI10.1038/nbt0988-1065

5)  Wozniak M.A. et al. “Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation” Neurosci Lett. Vol. 429(2-3), pages 95-100 (2007) DOI:10.1016/j.neulet.2007.09. 077

6) Velu V. et al. “Enhancing SIV-specific immunity in vivo by PD-1 blockade” Nature, Published online 10 December 2008 DOI:10.1038/nature07662