Infectious diseases that lead to long-term disability have been a persistent threat to humanity, but thanks to vaccination many have been confined to the annals of history. Viruses such as polio, hepatitis B, hepatitis C and the human papillomavirus can all lead to chronic disease, but modern medicine means they can all be effectively inoculated against. However, when it comes to the human immunodeficiency virus (HIV), which many epidemiologists still regard as being at pandemic levels globally, medical researchers haven’t been quite as successful.

HIV is classified into three stages. Acute HIV is defined by flu-like symptoms that occur in the days and weeks after infection, followed by chronic HIV, an asymptomatic stage that can last for several years. If untreated, chronic HIV eventually morphs into acquired immunodeficiency syndrome (AIDS).

AIDS gradually causes the immune system to fail, allowing opportunistic infections and cell abnormalities that the body would usually dispatch to thrive. For someone with AIDS, the common cold can cause the lungs to fail, or a mutant cell cluster can develop into a tumour far more easily than in a healthy person.

The disease didn’t gain mainstream attention in the medical community until 1981, when rare disease outbreaks began to be reported among gay men in Los Angeles, New York and San Francisco – namely, a cancer called Kaposi’s Sarcoma and an uncommon lung disease called pneumocystis pneumonia. By the end of the year, 337 cases had been HIV were reported. Of those patients, 130 were dead by 31 December.

Azidothymidine was introduced in 1987 as the first treatment for HIV, but it wasn’t until 1997 that highly active antiretroviral therapy (HAART) became the new treatment standard, leading to a 47% decline in death rates. HAART can’t rid the body of HIV, but effective treatment can reduce viral load to such an extent that it is considered ‘undetectable’. This means that standard HIV tests will not be able to detect the virus, it cannot be transmitted to another person and will not progress to AIDS.

HIV has transformed from a death sentence into a manageable chronic condition – but we still don’t have a vaccine.

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Why is it so hard to vaccinate against HIV?

After researchers at the US National Institutes of Health and the Pasteur Institute confirmed that HIV infection led to AIDS in 1984, US Health and Human Services Secretary Margaret Heckler claimed that a vaccine would be available within two years. However, the very nature of HIV complicated things immensely.

Frontline AIDS lead for prevention Matteo Cassolato says: “Unlike measles and other viruses, our immune system does not have the ability to naturally recover from HIV.

“Since people who acquire HIV can’t naturally clear the virus, we do not know what protection from HIV would look like in a person. If we knew that, vaccine researchers would know exactly what type of immune response the vaccine would need to elicit in our bodies to achieve protection from HIV infection.”

Vaccines are designed to train the immune system to protect against an infection by using killed or weakened pathogens, or derivatives from them like antigens or DNA. These killed or weakened pathogens trigger an immune response, teaching the body to recognise an attack by the infection in question in the future.

But the human body doesn’t produce the same kind of immune response to HIV as it does to pathogens that can be vaccinated against.

Cassolato says: “When any foreign pathogen, enters the body, what normally happens is that the immune system detects the virus and tries to control or eliminate it. Special cells called CD4 and CD8 recognise the virus as something that doesn’t belong and attack it.

“However, with HIV, CD4 and CD8 cells become the target of the HIV virus. By targeting for infection, the same cells that are supposed to protect us from it, HIV ends up blinding and weakening our immune system.”

Genetic diversity, mutations and no reliable animal model

The genetic diversity of HIV also makes it incredibly difficult to vaccinate against. The virus has the highest reported mutation rate of any biological entity, meaning there are many different strains of it out there. Researchers therefore need to be able to develop a vaccine that can protect from all the different strains of HIV, which would be incredibly challenging.

As well as multiple mutations, there are actually two species of HIV, both of which will eventually progress to AIDS if left untreated. HIV-1 is by far the most common strain of the disease, with around 95% of people infected with HIV worldwide having HIV-1. Meanwhile, HIV-2 is found mainly in West Africa where both viruses are thought to have originated, as it is much less virulent than HIV-1.

While HIV-1 and HIV-2 both have similar effects on the human body, they have only a 55% genetic sequence identity – enough that not all tests and treatments can work for both types. The case is likely to be the same for a vaccine.

The final key obstacle is that we do not have a reliable animal model to conduct HIV vaccine trials in, which is usually a key stage when it comes to this kind of medical research.

“Although forms of animal testing can be done, there are considerable limitations,” says Cassolato. “While there is a similar virus called Simian Immunodeficiency Virus, primates do not carry or transmit HIV itself, meaning it is difficult to compare how a vaccine works in primates to how it might work in humans.”

The story so far

The most successful HIV vaccine thus far was the RV144 trial, which concluded in 2009. Known colloquially as the Thai trial, it enrolled 16,402 men and women aged 18 to 30 and lasted almost six years. The randomised, double-blind study groups saw the volunteers receive either the HIV vaccine or a placebo, before going on to receive HIV testing every six months for three years to monitor their infection status.

RV144 volunteers received four injections of a vaccine called ALVAC HIV, and two of another vaccine called AIDSVAX B/E. ALVAX HIV contained genetically engineered versions of three HIV genes (env, gag and pol), while AIDSVAX B/E was composed of genetically engineered gp120, a protein which exists on the surface of HIV cells.

At the end of the study, the rate of HIV infection among volunteers who received the experimental vaccine was 31% lower than the rate of HIV infection in volunteers who were given a placebo. A 31% success rate was not enough for the Ministry of Public Health in Thailand to consider approving the vaccine, but it was the first evidence of any vaccine being at all effective in lowering the risk of contracting HIV.

“Although 31% is by no means a staggering figure, it indicated that a HIV vaccine was possible in protecting against the virus,” Cassolato says.

There are a number of HIV vaccine trials active today, but two of them – the Imbokodo study and the Mosaico trial – stand out from their peers.

Imbokodo and Mosaico: two trials give hope

The Imbokodo study, which launched in November 2017, is testing whether a vaccine developed by Janssen can safely and effectively reduce the rate of new HIV infections. The volunteers are all young women aged between 18 and 35, with study sites in Malawi, Mozambique, South Africa, Zambia and Zimbabwe. In eastern and southern Africa, women and girls account for nearly 60% of the HIV+ population.

Johnson & Johnson announced in July 2020 that all 2,600 participants in the trial had finally been vaccinated and said that initial results could be available as early as late 2021.

Pivoting off the Imbokodo study, the Mosaico trial will assess whether a very similar vaccine regimen can reduce immune responses against a variety of HIV strains among cisgender men and transgender people who have sex with other cisgender men or transgender people. Participants in the Mosaico study, which started in June 2019, are aged 18 to 60 and live throughout the US, Argentina, Italy, Mexico, Peru, Poland and Spain.

In Europe and the Americas, gay and bisexual men and transgender people are disproportionately affected by HIV – two thirds of new HIV diagnoses in the US come from gay and bisexual men, while an estimated 14% of transgender women in the country have HIV. But participants in the Mosaico trial will have to meet a number of strict criteria – simply being LGBT+ isn’t enough to be considered at-risk.

Within the past six months, they will have had to either: have had receptive condom-free anal or vaginal sex outside of a 12-month monogamous relationship with a partner known to be either HIV- or HIV+ and on HAART; have been diagnosed with rectal or urethral gonorrhoea, chlamydia or syphilis; have used stimulants such as cocaine or amphetamines; or had five or more sexual partners.

Both studies are evaluating a mosaic-based vaccine called Ad26.Mos4.HIV. The vaccine uses an engineered adenovirus vector, a harmless relative of the common cold, to deliver a ‘mosaic’ of carefully selected HIV antigens.

This combination of antigens should hopefully stimulate some sort of immune response in the study participants. The antigen combination used is not found in any individual HIV virus but rather is collated together from multiple viruses, so that the vaccine can protect against multiple global strains of HIV.

The studies differ when it comes to the booster injection stage. The viral envelope of HIV contains a protein called gp140. In the Mosaico trial, the third and fourth injections will be accompanied by a combination of gp140 from Clade C, the predominant type of HIV throughout Africa and Asia, as well as a mosaic of gp140 from other strains. Imbokodo’s regimen, on the other hand, will only contain Clade C gp140 proteins.

“The development of any vaccine is challenging, but HIV is particularly difficult due to the multiple barriers,” says Cassolato. “However, science and research are advancing at speed and it is certainly not impossible.”