Explained: Why Moderna’s mRNA candidate brings new hope for an HIV vaccine

Forty years since the HIV global epidemic began, new hope has arisen in the hunt for the so-far-elusive vaccine. The US pharmaceutical and biotech company Moderna, which rolled out the world’s first Covid-19 vaccine, recently announced human trials for two HIV vaccines. These are based on the same platform — mRNA — as Moderna’s Covid vaccine.

The human trials

Moderna will be trialling two versions of its vaccine candidate. This is the first mRNA vaccine against HIV to be trialled in humans. According to the US National Institutes of Health’s (NIH) clinical trials registry, 56 HIV-negative people between the ages of 18-50 have been recruited in the phase-1 trial.

There will be four groups in the first phase, with two receiving a mix of the mRNA vaccine versions and two receiving one or the other. The trial is not blind: Participants will know which group they are in.

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The two mRNA vaccines will eventually be used alongside another vaccine, developed by the International AIDS Vaccine Initiative (IAVI) and Scripps Research.

The hypothesis is that the two Moderna vaccines have the potential to prime a specific type of B-Cell to produce effective neutralising antibodies, and the other vaccine will stimulate them to do so. The study sponsored by IAVI and others is expected to run until May 2023, with the first phase lasting around 10 months.

HIV burden

HIV has claimed 36.3 million lives so far, according to the World Health Organization (WHO). There were an estimated 37.7 million living with HIV at the end of 2020.

There is still no cure. However, with increasing access to effective prevention, diagnosis and care, including for opportunistic infections, HIV infection has become a manageable chronic health condition in recent years.

According to the National AIDS Control Organization’s India HIV Estimation 2019 report, there were an estimated 23.48 lakh people living with HIV in 2019. Overall, the estimated adult (15-49) HIV prevalence trend has been declining in India since the peak in 2000, and has been stabilising in recent years.

The elusive vaccine

HIV tends to change its envelope so rapidly that it is difficult to provide any antibody cover. Additionally, the envelope proteins are covered by a sugar coating that affects generation of an immune response. said Dr R R Gangakhedkar, former director of National AIDS Research Institute, and former Head, Division of the Epidemiology and Communicable Diseases division of Indian Council of Medical Research (ICMR).

“An anti-HIV vaccine has been a challenge given the fact that it is a fast replicating virus and tends to mutate rapidly… Escape mutants are generated rapidly due to the high replication rate of HIV,” said Gangakhedkar, who is also a C G Pandit national chair, ICMR.

Even when antibodies are made, by the time they are produced, the virus rapidly evolves and the antibodies do not neutralise the virus. This rapid mutation allows the virus to escape the antibody response, said leading vaccine scientist Dr Gagandeep Kang. For example, the virus sequences of an untreated individual with HIV tested three months apart would show differences between the later and earlier viruses, she said.

Previous attempts

Dr Kang said previously inactivated forms of the virus and adenovirus vector-based vaccines have been tried, but have not worked. A handful of HIV clinical trials were very carefully set up and conducted, but were halted either for futility when vaccines did not work, or in the case of adenovirus vectored vaccine where there was a signal that participants were more susceptible to HIV, instead of being protected, she said.

“The most important challenges in HIV vaccine development has been the inability to identify the exact correlates of immune response that need to be stimulated to protect against HIV and the enormous diversity potential of the virus. Inducing broadly neutralising antibodies against HIV envelope protein and CD8 T cell responses has been the major focus,” said Dr Sanjay Pujari, infectious diseases consultant and expert member of the national Covid 19 task force.

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mRNA: way forward

The Moderna trial is different as it allows one to use technology to design and develop a vaccine really fast, Dr Kang said. It is similar to the Covid-19 vaccine development work so that the body’s cells can produce the virus’s spike envelope to trigger an immune response.

In the HIV context, the mRNA platform has shown promising results in vitro and monkey studies, and it would be useful to test it in human clinical trials, Dr Pujari said. The hope is that this platform has the ability to tweak the RNA to address emerging variants and their potential to escape immune response. “Until now the major challenge for the development of mRNA vaccines was lack of efficient delivery technologies. This has been overcome successfully with Covid-19 mRNA vaccines,” Dr Pujari said.

Preventive & therapeutic

Experts say two approaches can be considered for an HIV vaccine — a preventive and therapeutic one.

A preventive approach would have to check how many vaccinated people develop HIV post-vaccination, or whether the vaccinated ones can resist infection. A therapeutic approach would result in an immune response that would attack the infected cells and prevent further replication, Dr Kang said.

Therapeutic vaccines have been tried without success to achieve a functional cure. It would be interesting to study the performance of the mRNA platform in this context, Dr Pujari said.

For a therapeutic vaccine to work, it has to stimulate cells to generate broadly neutralising antibodies, Dr Gangakhedkar said. “While antiretroviral therapy controls the infection, one has to take drugs lifelong and there are side effects. A curative modality with a therapeutic vaccine and medicine can cure HIV. However, this has to be tested over a period of time, to assess whether the immune response is sustained,” Dr Gangakhedkar.

With HIV incidence having gone down, it reduces the risk of exposure to HIV. Moreover, use of other preventive measures adds to reduction in HIV incidence. These factors pose challenges in undertaking these trials and finding out whether or not the vaccine producing broadly neutralising antibodies actually prevents HIV infection, Dr Gangakhedkar said.

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