Scientific barriers render an HIV vaccine unfeasible at present time

Further efficacy trials may shift funding and focus away from much needed basic science.

Issue: March 2008

Significant strides continue to be made in the search for an effective HIV-1 vaccine, but researchers are still a long way from realizing that goal. Ronald C. Desrosiers, PhD, a professor of microbiology and genetics at Harvard Medical School and Director of the New England Primate Research Center, discussed the scientific obstacles to an HIV vaccine at The 15th Conference on Retroviruses and Opportunistic Infections, held recently in Boston.

“Sometimes, I think people forget – or choose to overlook – how daunting the task of a vaccine really is,” Desrosiers said. “First and foremost, we need to remember the defining hallmark of AIDS: HIV is the undisputed champion of persistent viral replication. Once HIV gets its foot in the door, it has an uncanny ability to replicate continuously without relent, no matter what the immune system throws at it.”

The persistence of HIV is a huge obstacle. Envelope spikes on the surface of virions are difficult for antibodies to access and neutralize. Furthermore, antibodies that will neutralize one strain of HIV typically are not effective against other strains. “HIV also encodes protein products that are directly involved in the evasion of intrinsic and adaptive immunity,” Desrosiers said. “And all the while, HIV is destroying the CD4 cells that are needed to orchestrate the antiviral immune responses.”

Sequence variability

Another enormous challenge to the development of a vaccine is the huge sequence variability in strains of the virus. To give an idea of the scope of HIV-1’s sequence variability, the variability for influenza A in the entire world in a given year is less than the sequence diversity in a single individual with HIV. “When we look at the circulating sequence diversity within an individual clade or among clades of HIV, we are left with quite a visible picture of how daunting the task is,” Desrosiers said. “What are we going to put into the vaccine to protect against this degree of sequence diversity?”

Superinfection poses another problem for vaccine development, as the immune response to one HIV strain does not always provide protection against others.

Early results from a study of 56 women in Kenya have shown that in 10 of 56 women, the immune response did not give protection against superinfection; sometimes this is the same clade of HIV, but it can be other clades as well. “In cases where the viral loads were initially low, superinfection was accompanied by an increase in the viral load to a higher set point,” Desrosiers said.

In another study, researchers looked at 13 married couples in which both members contracted with a different HIV strain. To date, three cases of superinfection among these couples have been documented.

Studies of vaccines against SIV in rhesus monkeys have given some reductions in viral load. But the best reductions seen have employed idealized, optimized laboratory conditions that do not necessarily reflect the virus in the field. In many cases, the viral challenge was cloned virus matched precisely to the sequences of virus present in the vaccine, and the challenges were conducted at or near the peak of the vaccine-induced immune response. Furthermore, Desrosiers said that the three efficacy trials in humans have been unsuccessful.

“In answer to the fundamental question, is an effective vaccine against HIV-1 feasible at the present time, my answer, sadly, is no,” Desrosiers said. “I don’t see how you can answer anything but no.”

Monkey studies

Data from the recent trial of Merck’s SIV-equivalent gag vaccine in rhesus macaques failed to show any efficacy; the researchers used cloned SIV that was matched in sequence to the vaccine material. No neutralizing antibodies were produced. “There have been statements to the effect that the monkey studies have misled us,” Desrosiers said. “The monkey studies have not misled us. There was no significant protective efficacy in monkeys, and no significant protective efficacy in human testing.”

The previous failures raise the question of whether any products currently in the development pipeline stand a reasonable chance of demonstrating efficacy. Desrosiers said that the barriers currently faced indicate that there is no rational basis for believing that such efficacy will be demonstrated. “I would go even further and add that there is little to be learned from efficacy trials for any of them, other than finding out that they do not have efficacy.”

Furthermore, repeated efficacy trials that result in failure may have ramifications beyond simply the failure of those products.

Desrosiers noted that dollars spent on manufacturing and testing products with little hope of efficacy could instead be poured into discovery research. The failures could also result in donor fatigue, with major funding sources potentially diminishing that funding for both vaccine trials and for basic science research. And finally, volunteer populations, especially in the developing world, may become suspicious of the trials, resulting in a reduction in volunteering for such trials.

“I feel that the ramifications associated with repeated efficacy trial failures should be a serious concern and something that we should try hard to avoid,” Desrosiers said. He added that although it is true that we might never know if a particular vaccine approach works until it is tested in humans, “given how dim the prospects are at the current time, and given the tremendous need for creative discoveries, there is a compelling rationale to be far more selective in bringing only products with significant promise to the clinic.”

The NIH role in HIV vaccines

Regarding where funding and efforts should be focused given the current limitations, Desrosiers said that the NIH has to some degree lost its way in the HIV vaccine arena. In 2007, the NIH spent $189 million on performance of HIV vaccine clinical trials, and considerable additional money went toward product development and product manufacturing.

This tactic of funding product development and testing was the result of a strategic decision to fill the void left by a lack of pharmaceutical industry efforts, Desrosiers said. “Pharma has gauged that given the current state of knowledge, a vaccine for HIV is not sufficiently feasible at the current time to warrant the dollars that it would take to try to develop one. I predict that when an HIV vaccine does become more feasible, pharma will jump on product development, product manufacturing, and clinical testing. And even if it doesn’t, that is the time that the NIH can jump in the fray and fill the void.”

If discovery research should be the primary efforts at this time, on what areas should they focus? One crucial step is to figure out how to elicit antibodies with potent broadly neutralizing activity. “It is hard for me to imagine a vaccine in the absence of neutralizing antibodies,” Desrosiers said. Some other areas on which to focus include identification of what constitutes a protective immune response, as well as research into certain monkeys that can have high viral load without getting sick; there may be some categories of human long-term non-progressors who also hold clues as to what constitutes a protective immune response.

Desrosiers said that with innovative thinking and novel ideas, progress can be made toward an HIV vaccine. “I feel strongly, however, that the discoveries and the creative ideas that are going to lead to a successful vaccine have not been made yet.” – Dave Levitan

For more information:

Desrosiers R. Scientific obstacles to an effective HIV vaccine. Presented at: The 15th Conference on Retroviruses and Opportunistic Infections; Feb. 3-6, 2008; Boston.