One of the biggest news stories at the AIDS Vaccine 2013 conference was the groundbreaking experiment in which half of a group of monkeys given a candidate monkey-HIV vaccine appeared to lose all trace of viral infection. This vaccine used genes from simian immunodeficiency virus (SIV), the monkey equivalent of HIV, contained in the shell of cytomegalovirus(CMV) – a ubiquitous virus from the herpes virus family.
As well as the CMV-based vaccine, other researchers are at an earlier stage of using experimental vaccines based on two other viruses of the herpes family – the varicella zoster virus (VZV) which causes shingles and chicken pox, and HHV-8 or KSHV, which causes the AIDS-related cancer Kaposi’s sarcoma. The vaccines use attenuated (weakened) versions of these viruses, which cause no disease but do stimulate an immune response, again with SIV genes packaged inside them to stimulate an immune response to that virus.
The rationale behind using viruses of this type is that they persist in the body, meaning that the anti-SIV immune stimulation they offer also persists, instead of fading over time.
A chicken pox/HIV vaccine?
Kelly MacDonald of the University of Toronto said VZV was a good candidate for a vaccine as there were already VZV vaccines licensed – against chicken pox (Varilrix/Varivax) in children, and against shingles (Zostavax) in people over 60. (Shingles is caused by a reactivation of latent VZV infection and is often seen in patients with compromised immunity caused by old age, HIV or for other reasons.) There are therefore already good safety data on these vaccines, meaning that if a VZV/SIV vaccine worked well in monkeys, a VZV/HIV vaccine for humans could be brought forward relatively quickly.
MacDonald’s team gave nine Cynomolgus (pig-tailed macaque) monkeys a single dose of an experimental VZV/HIV vaccine and nine others a placebo. They then waited a year: during this period, one of the vaccinated monkeys died, of an unrelated condition (lymphoma).
The team then gave the monkeys repeated challenges of SIV by rectal inoculation to simulate anal sex. Eight of the non-vaccinated monkeys developed normal SIV infections with high viral loads, while one controlled its infection spontaneously. Three of the eight vaccinated monkeys controlled their SIV infection, developing undetectable viral loads within a month of infection which are still undetectable a year later. The other five developed normal SIV infection, though they did have an approximately tenfold lower viral load from the second to the sixth month after infection, after which it rose to the levels in the non-vaccinated monkeys.
MacDonald found that the immune response generated by the vaccine was entirely due to high immune responses to SIV in CD8 and CD4 cells; it did not generate an antibody response.
Her team is currently looking at responses in other branches of the immune system, at whether the response is to a broad spectrum of SIV features (if it is, it means it could work against a wider variety of HIV strains) and at immune responses generated in the genital and rectal mucous-membrane cells. They now plan a larger animal trial using several doses of the VZV/HIV vaccine and several different strains of SIV infection.
MacDonald commented that a successful VZV/HIV vaccine could be a powerful therapeutic tool, not least because it could be given in place of the regular chicken-pox vaccine in childhood, possibly with a booster for teenagers. This could get round the social difficulties of having a vaccine against a sexually transmitted infection, which have affected the uptake of the hepatitis B and HPV (human papillomavirus) vaccines.
A Kaposi’s sarcoma virus-based vaccine?
Meanwhile Ron Desrosiers of Harvard Medical School has also been giving monkeys a herpes virus-based vaccine – only this time his vaccine is based on HHV-8 or KSHV, (the Kaposi’s sarcoma herpes virus), or at least a monkey analogue of it called rhesus monkey rhadinovirus (RRV).
In a previous experiment, Desrosiers gave six monkeys an RRV/SIV vaccine and then challenged them with SIV. All six monkeys became infected and developed SIV viral loads, but with a viral load that was persistently 50-fold (1.7 logs) lower than non-vaccinated monkeys.
After manipulating his RRV/SIV vaccine to produce a strong antibody as well as a cellular immune response, Desrosiers repeated the experiment this year, vaccinating six monkeys in March with RRV/SIV and six others with a placebo and challenging them with SIV three months later.
As with MacDonald’s study, one placebo-receiving monkey spontaneously controlled its SIV while the other five developed normal SIV infection.
Four out of the six vaccinated monkeys developed persistently undetectable viral loads after a small ‘blip’ two weeks after infection and one of the other two developed an infection with a viral load 100-fold (2 logs) lower than the final vaccinated monkey, which had a viral load as high as the unvaccinated monkeys. This represents, then, a 67% efficacious vaccine, but the results presented only go to eight weeks post-infection, so it is not yet clear how long the vaccine’s effect will persist.
The idea of a vaccine based on a cancer-causing virus (even if it is altered so as not to cause disease) will raise inevitable safety concerns – as has the CMV-based vaccine, because CMV can cause disease in unborn babies and people with very low immunity. Both these vaccines may therefore take a while to develop, even if their success can be repeated in humans, as they are likely to need stringent safety checking.
A new vaccine for tuberculosis?
The advantage of using a herpes virus vector, however, is that it is very versatile: antigens (immune-stimulating components) from all kinds of micro-organisms could be wrapped inside a herpes virus shell.
A propos of this, Louis Picker, developer of the CMV-based vaccine, had one more surprise to announce: in an initial experiment, he had successfully protected several monkeys from a virulent form of monkey tuberculosis (TB) using a vaccine with a CMV shell containing antigens from the TB bacterium.
The TB vaccine was given to monkeys by itself and also in combination with the existing, not very efficacious, BCG vaccine. Only two out of seven monkeys given the CMV/TB vaccine developed severe lung disease when subsequently infected with TB, compared with all eight unvaccinated monkeys, and one vaccinated monkey did not develop TB symptoms at all. (Adding in BCG made no difference to the efficacy of the TB vaccine, or may even have made it poorer: only two out of seven vaccinated with this combination did not develop severe lung disease.)
Picker presented X-ray scans showing that the lungs of vaccinated monkeys stayed almost clear of TB lesions compared with rapid disease progression in unvaccinated ones.
Clearly, herpes virus-based vaccines may have a promising and versatile future in providing protection against a number of diseases: Picker said he may also investigate the possibility of a CMV/malaria vaccine.
Willer DO et al. (presenter MacDonald KS) Protection of Cynomolgus macaques from pathogenic SIV following vaccination with varicella-zoster virus based vaccines. Thirteenth AIDS Vaccine Conference, Barcelona, abstract OA04.05, 2013.
Shin Y et al. (presenter Desrosiers RC) Impressive vaccine protection against SIVmac239 by recombinant gamma-2 herpesvirus. Thirteenth AIDS Vaccine Conference, Barcelona, abstract S03.05, 2013.
Picker L Pre-clinical development of Cytomegalovirus vectors. Thirteenth AIDS Vaccine Conference, Barcelona, abstract S03.03, 2013.
Webcasts and slides from the AIDS Vaccine conference can be viewed at http://www.aidsvaxwebcasts.org/