The only HIV vaccine in a late-stage trial has failed, researchers announced Wednesday, dealing a significant blow to the effort to control the global HIV epidemic and adding to a decades-long list of failed attempts.

Known as Mosaic, the trial was the product of a public-private partnership that included the US government and pharmaceutical giant Janssen. As of 2019, it has sold out in eight countries in Europe and the Americas, including the US.

He study leaders decided to suspend the mammoth research effort after an independent data and safety monitoring board reviewed the trial findings and saw no evidence that the vaccine reduced participants’ rate of HIV acquisition.

“It’s obviously disappointing,” Dr. Anthony Fauci, who as longtime director of the National Institute of Allergy and Infectious Diseases (NIAID) was an integral partner in the trial, said of the vaccine’s failure. However, he said, «there are many other approaches» early in the line of HIV vaccine research that he sees as promising.

“I don’t think people should give up on the HIV vaccine field,” Fauci said.

fauci previously mentioned he did not want to withdraw from NIAID until an HIV vaccine was proven to be at least 50% effective. good enough, in his opinion, for a global implementation. Instead, he retired from his post at the end of last month with this dream unfulfilled.

In addition to NIAID and Janssen, which is a division of Johnson & Johnson, the trial was conducted by the HIV Vaccine Trials Networkwhich is based at the Fred Hutchinson Research Center in Seattle, and the US Army Medical Research and Development Command.

Mosaico’s lack of effectiveness was not unexpected, experts said, given the recent failure, announced August 2021, from a separate clinical trial, called Imbokodo, that tested a similar vaccine among women in Africa. Between the two trials, NIAID spent $56 million, according to an agency spokesperson.

Vaccines tested both trials used a common cold virus to deliver what are known as mosaic immunogens, which were intended to elicit a robust and protective immune response by including genetic material from a variety of HIV strains prevalent worldwide, according to the national institutes of health. Mosaic included an additional element intended to amplify the immune response.

The Mosaico participants, who ranged in age from 18 to 60, received four injections over 12 months of either the vaccine or a placebo. The follow-up board found no significant difference in the rate of HIV acquisition between the two study groups.

Fauci said a critical limitation of the Mosaic vaccine was that it elicited what are known as non-neutralizing, rather than neutralizing, antibodies to HIV.

«It is becoming increasingly clear,» he said, «that vaccines that do not induce neutralizing antibodies are not effective against HIV.»

Promising HIV vaccine innovations, including efforts that build on the cutting-edge mRNA vaccine technology behind some of the coronavirus vaccines, may hold the key, Fauci said.

The critical problem that has plagued HIV vaccine research for decades, Fauci noted, is a crucial weakness that the virus already successfully exploits: The natural immune response to infection is not sufficient to thwart the virus.

“So the vaccines would actually have to work better than natural infection to be effective,” he said. «That would be a very high bar.»

A decades-long effort

In 1984, following the discovery of HIV as the cause of AIDS the previous year, President Ronald Reagan’s health secretary, Margaret Heckler, famously stated a vaccine for the virus would be available within two years.

In the decades since, there have been nine late-stage clinical trials of HIV vaccines, including Mosaico and Imbokodo, plus one, called PrEPVac, that’s still going on in Africa. However, the vaccine in PrEPVacc is not considered to be on a direct path to licensing if it demonstrates efficacy. Only one of these vaccines has shown any efficacy, and only at a modest level, not considered robust enough for regulatory approval, in a trial conducted in Thailand between 2003 and 2006, the findings of which were published in 2009.

In the years since, a phalanx of researchers from around the world have studied the Thai trial in the hope of developing knowledge that will inform future HIV vaccine development.

The year-long effort to design the Imbokodo and Mosaico vaccines was based in part on an attempt to build on the modest success of the Thai trial.

“We were hoping to see some sign of efficacy from this vaccine,” said Dr. Susan Buchbinder, an epidemiologist at the University of California, San Francisco, who co-led the Mosaico trial. Promisingly, as in the Imbokodo trial, there were no glaring concerns about the vaccine’s safety, she added.

Buchbinder said it’s too soon to determine the reasons behind the failure of the Mosaico vaccine. His team will analyze blood samples from the participants in the coming months to investigate. They will also look to determine if there were subgroups of participants among whom the vaccine showed some efficacy. As with the Thai trial, the hope is to channel the research findings into the future development of an HIV vaccine.

Other HIV prevention tools

Jennifer Kates, director of global health and HIV policy at the Kaiser Family Foundation, said the trial failure is a «reminder marker of just how elusive an HIV vaccine really is and why this type of research continues to matter.»

«Fortunately, there are already a number of highly effective HIV prevention interventions,» Kates added. “The challenge is to scale them up to reach everyone who is at risk.”

Pre-exposure prophylaxis, or PrEP, in which people at risk of contracting HIV take antiretroviral drugs before possible exposure to the virus, is highly effective in prevention infection, but it is still very underused In the USA and around the world

Also, research published in the mid 2000s demonstrated that voluntary medical male circumcision reduces the risk of female-to-male HIV transmission by approximately 60%. This led to a major effort to promote circumcision in sub-Saharan Africa, home to two-thirds of the world’s HIV cases.

In more recent years, an antiretroviral infused vaginal ring has proven effectiveness to reduce women’s HIV risk. Initial efforts are underway to introduce it to African nations.

And, of course, there’s the old mainstay: condoms.

Globally, an estimated 38.4 million people were living with HIV in 2021, according to the Joint United Nations Program on HIV/AIDS. Currently, about 1.5 million people contract the virus annually, a number that has more than halved since its peak in 1996.

It is at least theoretically possible, though extremely challenging, to control HIV without a vaccine. Fortunately, successfully treating HIV eliminates the risk of transmitting the virus through sex. Therefore, HIV transmission has declined in recent years in large part due to the spectacular expansion of antiretroviral treatment of the virus, which in 2021 reached 28.7 million people.

Mosaic was particularly difficult to design ethically due to the advent of PrEP, which was first approved in the US in 2012. To prove that a vaccine works, researchers must recruit participants who remain at substantial risk of contract HIV over time. So Mosaic first offered PrEP to those seeking to enroll in the trial and only accepted as participants those who outright refused preventive therapy despite their HIV risk.