Scientists have tested a trial vaccine that protects rhesus monkeys against infection from a potent form of the simian immunodeficiency virus (SIV), a distant relative of HIV, the virus that causes AIDS in humans. Monkeys that received the vaccine were more than 80% less likely to become infected when exposed to SIV than monkeys that received a dummy shot.

The new research, led by Harvard Medical School and reported online in the journal Nature on 4 January, has raised hopes that an effective HIV/AIDS vaccine is now a significant step closer because it offers vital clues as to which ingredients may succeed in humans and it identifies new HIV vaccine candidates to test in human trials, which are already being set up.

Lead author Dan H. Barouch, Chief of Vaccine Research at Beth Israel Deaconess Medical Center (BIDMC), is also a a Professor of Medicine at Harvard Medical School and faculty member of the Ragon Institute of MGH, MIT, and Harvard. He told the press:

“This study allowed us to evaluate the protective efficacy of several prime-boost vaccine combinations, and these data will help guide the advancement of the most promising candidates into clinical trials.”

Barouch and colleagues treated groups of rhesus monkeys (Macaca mulatta) with several different “prime-boost” vaccine combinations.

This type of vaccine has two stages: the “prime” and the “boost”. The prime is a virus genetically engineered to include some DNA from SIV genes. This is given first. The second stage, the “boost”, given about six months later, contains another virus expressing the same genes.

Then six months after the second shot (the boost), the researchers infected the monkeys with a strain of SIV that was different to the one in the vaccine, and against which they already knew the monkeys’ immune system would not be able to respond strongly.

The combination that worked best at preventing infection was one where the prime was an adenovirus and the boost was a modified-pox-virus.

Three quarters of non-vaccinated monkeys developed SIV after one exposure compared to only 12% that received this most effective of the combinations.

In their Nature paper, Barouch and colleagues describe not only how the new vaccine combinations gave partial protection against SIV in rhesus monkeys, but also how optimal combinations substantially reduced the amount of virus in the blood of animals that became infected.

A statement from BIDMC also highlights that previous preclinical trials of vaccine candidates have “typically shown post- infection virologic control, but protection against acquisition of infection has previously only been reported using less rigorous viral challenges”.

But, the new combinations tested in this latest study resulted in over “80% reduction in the per-exposure probability of acquisition of infection against repetitive challenges of SIV”.

Further analysis also revealed insights into the underlying immune components that may lie behind the protective effects invoked by the trial vaccine, what the authors refer to as the “immune correlates”.

They showed that antibodies to Env (the envelope protein that coats the outside of the virus) linked to protection against acquiring infection, whereas both T cell and antibody responses linked to control of the virus post-infection.

Senior author COL Nelson Michael, Director of the US Military HIV Research Program at the Walter Reed Army Institute of Research, said:

“These distinct immunologic correlates likely reflect fundamentally different requirements to block establishment of infection compared with controlling viral replication after infection.”

Barouch said the study clearly shows that including Env in the vaccine is “beneficial”, and that a high degree of protection is afforded against stringent virus challenges, even in the absence of “high levels of tier 2 neutralizing antibodies”.

The results of the study have spurred collaborators to push the Ad26/MVA prime-boost vaccine candidate into clinical development. Clinical trials to test this HIV vaccine combination in healthy human adults are already at the planning stage, with trials sites being set up in the US, East Africa, South Africa, and Thailand.

Written by Catharine Paddock PhD