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November 2021

Examples of media coverage: 

  1. Research team develops vaccine that kills HIV in monkeys – The Asahi Shimbun, November 9, 2021
  2. A New Vaccine Kills HIV in Monkeys. And It’s Coming to Humans in 5 Years – Interesting Engineering, November 11, 2021
  3. HIV breakthrough offers hope as new vaccine crushes virus in stunning trial results – Daily Express, November 12, 2021

Original source:

  1. Journal article: Long-term protective immunity induced by an adjuvant-containing live-attenuated AIDS virus – npj Vaccines, October 22, 2021

TAG’s commentary:
The focus of this published study is preventive vaccination, but the authors of the paper also suggest their results may have implications for HIV cure research. The study, which tested a vaccine approach in macaque monkeys, has drawn considerable media attention.

As can be seen from the headlines above, media stories have particularly highlighted that the vaccine may have promoted clearance of an HIV-like virus in some of the macaques.

There are multiple issues to bear in mind when considering the results of this study, none of which are mentioned in the news stories. The two most important are:

  • Similar results have already been achieved in macaques with a potentially safer candidate, which is already being evaluated in human trials.
  • It is extremely uncertain whether the type of vaccine used in the study—a live attenuated vaccine—will ever be considered safe enough to test in people.

The experiment tested a live attenuated hybrid virus made up of elements of HIV and simian immunodeficiency virus (SIV), the monkey equivalent of HIV. These hybrids are known as SHIVs. Live attenuated means that the virus can replicate but is weakened, with the aim of preventing it from being able to cause disease.

The researchers added an immune-stimulating protein derived from mycobacteria to the SHIV, creating a virus they refer to as SHIV-Ag85B. The live attenuated SHIV-Ag85B virus was then tested as a vaccine.

The test involved administering SHIV-Ag85B to a group of macaques, and later exposing them to a different SHIV that has the capacity to cause disease (SHIV89.6P). In vaccine research, this is known as a challenge experiment.

Receipt of the live attenuated the SHIV-Ag85B vaccine was associated with control of the SHIV89.6P challenge virus in almost all the macaques. A subset of these macaques (57%, just over half of them) later showed evidence of having cleared the SHIV89.6P virus.

Perhaps the most important information to know is that similar results have previously been obtained in macaques with a vaccine candidate that uses a weakened form of cytomegalovirus (CMV) as a vector to induce immune responses against SIV.

In those studies, vaccination prior to exposure to the highly pathogenic SIVmac239 virus was associated with strict control of viral replication in 50% of macaques. Careful examination of a subset of the animals provided evidence that SIVmac239 had been cleared.

While there are some concerns about whether the CMV vector will prove safe, it is already being evaluated as an HIV vaccine platform in a phase I clinical trial.

The rate of virus clearance may appear slightly higher in this report on the SHIV-Ag85B vaccine, but there is a critical caveat: the hybrid SHIV89.6P virus used to challenge the animals is known to be far easier to control than SIVmac239.

The authors of the paper acknowledge this, stating: “protection against CXCR4 tropic viruses such as SHIV89.6P is easier than that against CCR5 tropic viruses.” But they also appear to subsequently contradict themselves by claiming that they “used a stringent animal model involving a pathogenic SHIV.”

The reasons why SHIV89.6P cannot be considered a stringent test of vaccine efficacy are explained in a commentary from 2002, and these concerns were borne out by subsequent studies. For example, an HIV vaccine developed by Merck demonstrated good results in macaques when tested against SHIV89.6P but failed to show any efficacy in human trials (furthermore, there was evidence of an increased risk of HIV infection among some recipients). As a consequence, most HIV vaccine researchers no longer use SHIV89.6P as a challenge virus in macaque studies. 

Additionally, as far back as the early 1990s, live attenuated SIV vaccines have been tested in macaques and shown complete protection against a highly pathogenic SIV challenge in some instances. The reason they haven’t been tested in people is because it’s considered too risky.

Risks include loss of attenuation leading to disease, which has been reported in newborn macaques. SHIV-Ag85B has so far only been tested in adult macaques. Another concern is that live viruses (whether SIV, SHIV or HIV) integrate into the genetic code of cells, which may in rare cases be able to promote cancer.

The authors of the SHIV-Ag85B study state that their research “may lead to the development of a vaccine for AIDS virus infection” but offer no explanation as to why they think their live attenuated vaccine approach would be safe enough to be tested in humans.

The news coverage goes further, reporting that “the team’s goal is to begin clinical testing on humans within five years” (as mentioned in one of the headlines) and “the research team plans to create vaccines by using HIV removed from patients undergoing drug treatment.”

At the current time, it appears highly unlikely that regulators (like the US Food and Drug Administration, or the equivalent in Japan where this research was conducted) would allow a live attenuated HIV vaccine to be administered to healthy individuals.

The researchers also claim that their results may offer “new opportunities to develop a better therapeutic cure.” It’s possible that the regulatory hurdles to administering a live attenuated vaccine to people with HIV might be lower than those for HIV-negative people. However, the CMV-based SIV vaccine mentioned earlier that demonstrated similar results in the preventive context was also tested as a therapeutic vaccine in macaques, and did not show efficacy.

In summary, the results of the study are encouraging because they add to the evidence that clearance of cells infected with viruses similar to HIV may be possible under some circumstances. But both the paper and the associated news coverage are likely overselling the prospects for translating the results into a preventive or therapeutic HIV vaccine suitable for use in humans.

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