HIV epidemic control: the 40-year quest for a successful vaccine continues

Professor Gray, one of 35 A-rated scientists in South Africa, was giving an update at the 11th AIDS conference last week (June 20th-23rd), on the hard yards made in the elusive design of a successful HIV vaccine.

“The rapid integration of the virus after acquisition and the inability for early therapy to interrupt this means that the goal of an HIV vaccine must be to prevent acquisition or eradicate recent infection. It takes 50 to 100 times more neutralising antibody to inhibit HIV than it does SARS Cov-2," she said.

Previously, the fastest a vaccine took to go from development to deployment was the mumps vaccine, (in the 1960s), – some four years. Shattering that record, the Covid (SARS Cov 2) vaccine was available for commercial production in less than a year – after ongoing HIV vaccine work was pivoted to this end. Vaccines generally take five to 15 years to become viable and commercially available.

Gray said making an HIV vaccine was scientifically hard. “It’s likely the hardest antibody mediated vaccine in the virological world, but it’s still vitally necessary.”

There are 8,45 million South Africans estimated to be living with HIV, (PLHIV’s), of whom 76% are on ART. The program suffered major setbacks during Covid. Life-long ARV drug-taking enables PLHIVs to live a near normal life.

It boosted the SA population’s average life expectancy from 54 to 65 years within two years of the (politically delayed) ARV rollout. Over the years, earlier and earlier treatment initiation has allowed near-to-normal life
expectancy.

Gray described the HIV vaccine infrastructure as, "the NASA of COVID-19 vaccine development.”

She said the immunogen design for an HIV vaccine was directed at making broadly neutralising antibodies to more than one site. Currently, this required different immunogens for each site – an “epitope-specific” vaccine.

“We have a rich scientific portfolio in approaches and our scientific challenge is to put these different approaches into a coherent vaccine regimen. The addition of the mRNA platform is necessary to iterate the informed empiricism needed to develop an effective vaccine regimen. It doesn’t mean it’s the only or final platform in achieving success, but it’s a necessary tool to get there,” she explained.

There had been four HIV vaccine efficacy studies since 1984 and progress accelerated over the past eight years during which the passive infusion of a broadly neutralising antibodies, (BNAB’s), provided evidence of protection in vaccine sensitive viruses.

She listed the scientific challenges in constructing an effective HIV vaccine:

“One needs to prevent acquisition or cure early established disease – a much higher bar than traditional vaccines, such as COVID-19. The genetic diversity of the virus is greater than any other pathogen. The envelope is less immunogenic than any other virus envelope proteins; perhaps because of its glycan shield.”

(The glycan shield plays a critical role in hiding the S protein surface from molecular recognition.)

Many parts of the HIV trimer created “diversionary antibodies” and, “we don’t have a systematic approach to define these and “cut them out.”

There were far fewer trimers (a membrane fusing ‘machine’ responsible
for receptor recognition and viral fusion with CD4+ T cells – the sole target
for neutralising antibodies,) on the surface than most viruses.

“It’s a very “bald” virus and neutralising antibodies cannot cross link,” she explained.

Gray added that because there were no human cures for HIV, there were no immunological models to mimic.

“It takes a global village to make an HIV vaccine,” she said of the bid.

An impressive HIV control record

Also presenting in the plenary session entitled, “Reconnecting -are we on track towards epidemic control?” was Dr Haroon Moolla, a senior research officer, public health medicine registrar and statistical modeller at the University of Cape Town.

He said ART coverage in SA among those diagnosed had gone from under 50% in 2013 to 77,4% this year, while HIV incidence had dropped from 0,7% in 2013 to 0,3% this year – and was projected to reach 0,23 by 2030.

SA’s HIV achievements have been globally lauded.

Moolla said statistical modelling revealed that without HIV testing, ART or condoms, HIV incidence rates in adults aged 15-49 years would have risen from zero percent in 1985/6 to around 1,8% in 2017/18.

AIDS deaths had dropped from 85 000 in 2013 to just under 50 000 last year.

The mother-to-child HIV transmission rate dropped from 6,2% in 2013 to 3,8% last year, thanks to the roll-out of Nevirapine, the antiretroviral prophylaxis for infants. Without any intervention, mother-to-child transmission rates of HIV would range from 15% to 45%.

The percentage of circumcised males aged 15-49 had risen from 41% in 2013 to 62% last year. Trials have shown that male circumcision can reduce a male’s chances of acquiring HIV by up to 60% during heterosexual contact with HIV-positive female partners.

Pre-exposure prophylactic coverage among female sex workers had risen from 13% in 2017 to 20% last year, Moolla said.

HIV prevalence, measured in June last year, was highest in KwaZulu Natal at 17,5% (highest ART coverage at 84% of those diagnosed), followed by Mpumalanga at 15,7%, (second highest ART coverage at 80% of those diagnosed), the Free State at 14,9%, (79,9% ART coverage of those diagnosed), the Eastern Cape at 13,4%, (74,8% ART coverage of those diagnosed).

South Africa’s overall HIV prevalence in June last year stood at 13,1%, (77,4 % ART coverage of those diagnosed).

Moolla said he was busy calibrating the data from last year’s HSRC household prevalence survey, data from key populations, plus province-specific data on HIV testing into his statistical model which would be available shortly.

He said that despite dramatic improvements in incidence and mortality, there was an urgent need to extend ART coverage and probe the role of specific interventions in controlling the epidemic.

Exciting drug advances

Professor Francois Venter, Head of Ezintsha, a research group at Wits University investigating better first-line ART options, said that over the last five years Dolutegravir had very successfully replaced Efavirenz and was proving to be, “a massive public health success.”

It was showing far fewer and less severe side effects, had resolving neural tube defect signals, had far better persistence and was showing ‘a remarkable resistance profile.”

“We’re still awaiting any meaningful resistance, years and tens of millions of patients later,” he enthused.

One concern was that the new drug had seen less take-up in the private sector.

Venter said the greatest leap forward in ARV drug design were the concepts of longer acting, formulations, “a loose term for anything lasting a week or more,” and those that could be taken orally or were injectable (intramuscular or subcutaneous), or implantable.

In practice there were only two formulations registered by the FDA: Cabotegravir with Rilpivirine for treatment – two separate intramuscular injections. The downside was that administration was painful, (different sites in the buttocks), there were cold chain issues, appropriately trained health workers were needed, and they were expensive.

Another option was Lenacapavir, subcutaneously administered six-monthly for treatment – but with daily tablets in experienced patients. While studies were promising, researchers were battling to find a partner drug. Another likely candidate was Islatravir, a weekly tablet for treatment (dropped monthly), paired with daily tablet, including Lenacapavir.

“There are many, many other compounds – none near completion, so it’ll be at least two to three years before registration,” he said.

Of the registered formulations he enthused, “people with HIV love this! Despite pain. And it includes men – imagine giving a patient 28 tablets for six months? Or six tablets! Or one injection! Or an implant for a
year!”

He said the combination was also showing success in drug-using populations, but an operational question was “whether they’ll love coming more often.”

He said the thorniest issues included ‘the usual’ intellectual property wrangles, cost, the de-prioritisation of women in research (‘luckily” PrEP studies were providing pregnancy data), and there were long ‘tails’ with integrase resistance and cabotegravir – though studies were addressing this.

Venter said the new drugs are exciting, "but are not going to fix systems."

Long-acting formulations would stress inflexible primary care and urgent plans needed to be made for weight gain, while creativity and activism were needed for integration and improved systems.