Wednesday, August 19, 2015

Vaccine for the Infectious Kiss


In an average lifetime of an individual, what would be the average number of infections encountered is a difficult question to ask. None has a crisp answer. But if you had ask what is the most common infection that majority of the world population is likely to encounter, that had be a more easier question to answer. Of these, there are some viruses, that is encountered and a good majority of them is the Human Herpes group of viruses. One among them- Epstein Barr Virus (or just refer to it as EBV) has been of great interest. It is estimated that about 95% of the world population has EBV infection. Interestingly, less than 20% of them show any signs of infection. A portion of these show up with infectious mononucleosis (IM). 

Fig 1: EBV Life cycle. Source
EBV is a member of Human Herpes virus gamma subgroup (HHV-4). The gamma group of viruses are in general slow reproducers, often associated with lymphocytes and involved in long latency periods. The structure of EBV is a typical herpes. 85 genes, large enveloped virus. The virus can infect B cells and epithelial cells, though studies suggest that the preference is the B cells. gp350 interaction with CD21 forms the cellular entry path. EBV can also enter CD21 negative cells via interaction with CD35 through viral gp350/220. In case of epithelial cells, the virus can enter the cells via BMRF-2 interacts with cellular β1 integrins. It has been suggested that there are several other alternate routes though there is lack of evidence. Apparently, EBV is transmitted from person to person via saliva which mostly is due to kissing (One of my teacher would joke about it saying it ain't a kissing infection rather a smooching infection).

Fig 2: Antibody response in patients
with Infectious mononucleosis.
Immunologicaly, EBV induces antibody production. EBV produces different antigens at different time points of infection, and hence the antibody titre varies. The antibody response in these cases is of diagnostic interest. From the vaccine point of view, the best immune response would be blocking antibodies, one's which doesn't allow EBV cellular entry. There have been several vaccine tested till date on non human models. Most of the studies have not progressed beyond Phase I. Only one vaccine from the GSK has made it to Phase II. The vaccine is a GP350/AS04 containing Recombinant gp350 purified from the supernatant of Chinese hamster ovary cells expressing a gp350/220 gene construct with splice-site mutations that prevent population of the gp220 isoform (MSTOP gp350). The study had 181 volunteers. The vaccine had reduced IM by 78% but didn't prevent the primary infection. This is not a surprise, as I described there are alternative routes of infection.

Fig 3: Fit model of gp350 D123
protrusion on ferritin
nanoparticle. Source
A new study by Nabel etal has used another approach. The team created gp350 containing nanoparticles as the immunogen. The basic construct contained ferritin or encapsulin stably containing D2H6O or D123 (truncated variants of gp350). These self assembling particles was then tested for its ability to induce neutralizing antibodies in mice and non human primate models. As can be seen from the paper, the response is quite remarkable. Further, the use of ferritin and encapsulin had stabilizing effect on the truncated EBV proteins which is a good news. At this point this is just another vaccine candidate. But that finding that this version was better than the soluble native version with potent neutralizing activity is encouraging.

It has been questioned that what would constitute a ideal EBV vaccine. Of course the straight answer is 100% efficacy in preventing primary infection. However, considering that EBV in most people doesn't do anything much, a vaccine which protects well against the IM should be a good deal, at least for a start. Of course the best thing possible is not to ever kiss.
Sokal EM, Hoppenbrouwers K, Vandermeulen C, Moutschen M, Léonard P, Moreels A, Haumont M, Bollen A, Smets F, & Denis M (2007). Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. The Journal of infectious diseases, 196 (12), 1749-53 PMID:18190254
Kanekiyo M, Bu W, Joyce MG, Meng G, Whittle JR, Baxa U, Yamamoto T, Narpala S, Todd JP, Rao SS, McDermott AB, Koup RA, Rossmann MG, Mascola JR, Graham BS, Cohen JI, & Nabel GJ (2015). Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site. Cell PMID:26279189Cohen, J. (2015). Epstein–barr virus vaccines Clinical & Translational Immunology, 4 (1) DOI: 10.1038/cti.2014.27

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