When Will We Have an HIV Vaccine?

Researchers Exploring Novel Combination Strategies to Eradicate HIV

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It was in 1984 when then-Secretary of Health and Human Services Margaret Heckler boldly predicted that an AIDS vaccine "would be ready for testing in about two years."

Now, more than 30 years into the epidemic, we have yet to see anything approaching a viable candidate, either to prevent viral transmission or to provide people with HIV the ability to control the virus without the use of drugs.

Does that necessarily mean that we've gotten nowhere in all that time?

While it may seem that way, with a seemingly endless string of public failures, the truth is that we had very few tools back in the 1980s and 90s to unlock the genetic secrets of the virus.

Today, with more and more of these tools at our disposal—from advanced 3D electron microscopy to next-generation gene editing—are we any closer to finding the elusive cure for HIV?

Challenges and Limitations of Early Research

The fact is that, even in 1984, researchers were well aware of the challenges they faced in developing an effective vaccine. In a Congressional report submitted by the Office of Technology Assessment, investigators noted that:

"Neither live virus vaccines for AIDS, nor whole inactivated preparations containing the genetic material of the AIDS virus, currently hold much promise," while adding that "if genetic mutations (of HIV) are significant enough...it will be difficult to develop an effective vaccine."

Adding to the dilemma was the fact that many of the technologies needed to develop a vaccine were largely experimental at the time, particularly the recombinant DNA techniques used in modern vaccine research.

But even with these early failures, researchers gained much knowledge as to the limitation of traditional vaccine design, namely

  • that so-called "whole-killed" vaccines (in which HIV is physically destroyed either by antibiotics, chemicals, heat or radiation) do not spur a relevant immune response.
  • that simply activating the body's natural immunity is insufficient since HIV kills the very cells that orchestrate an immune response (CD4 T-cells), leaving the body incapable of mounting an effective defense.
  • that the  high rate of mutation provides HIV with enormous genetic diversity that makes creating a single vaccine—one that can neutralize all variant strains of HIV—incredibly difficult, if not impossible.

The Rise of Therapeutic Vaccines

In recent decades, much research has been focused on the development of therapeutic vaccines. In short, if a vaccine candidate is unable to fully prevent infection, it may slow or even stop the progression of the disease in those already infected. For a therapeutic vaccine to be considered effective, authorities suggest that it would have to stop at least 50% of infections in those inoculated.

We've edged closer to that target in recent years, none more so than RV144 trial in 2009. This  Thai study, which combined two different vaccine candidates (both of which had underperformed on their own), demonstrated a modest 31% reduction in infections between participants in the vaccine group versus those in the placebo group.

That trial was soon followed by the RV505, which was meant to expand upon those results by combining a "priming" vaccine with a "boosting" vaccine housed within a disabled adenovirus (a  common type of virus associated with a cold). But instead, the trial was stopped prematurely in April 2013 when it was reported that more vaccine participants were infected than non-vaccine participants.

In the aftermath, many in the research community expressed concerns about the void left by the RV505, suggesting that it could very well set back the vaccine initiatives for decades.

What Is the Future of HIV Vaccine Research?

Despite the failure of the RV505, a number of smaller trials continued to investigate various primer/booster strategies. The first of these, the RV305, has recruited 167 HIV-negative participants from the earlier RV144 trial in Thailand. The aim of the research is to determine whether additional booster inoculations will increase protection beyond the 31 percent mark.

A second study, known as the RV306, will investigate the efficacy of different types of booster vaccines when used in conjunction with the original RV144 vaccines.

Meanwhile, much of recent research has been focused on so-called "kick-kill" strategies. The combination approach aims to use specialized drug agents to kick HIV from its hidden cellular reservoirs while a second agent (or agents) effectively kills the free-circulating virus. 

There have been some successes in clearing the viral reservoirs, including the use of HDAC inhibitors (a type of drug classified as an antipsychotic). While we have much to learn about how widespread these hidden reservoirs may be, the approach seems promising.

Similarly, scientists have made headways in the development of immunologic agents able to spur the body's natural immune defense. Central to this strategy is so-called broadly neutralizing antibodies (bNabs)—specialized proteins able to effect eradication of a broad range of HIV subtypes (as opposed to non-broadly neutralizing antibodies able to kill one strain).

By studying elite HIV controllers (individuals with an innate resistance to HIV), scientists have been able to identify and stimulate the production a number of promising bNAbs. However, the central question remains: can scientist stimulate an ample response to kill HIV without hurting the infected individual? To date, advances have been promising, if modest.

In their totality, these trials are considered significant as  they build upon lessons learned from previous vaccine failures, namely :

  • Failure does not always mean defeat. The AIDVAX vaccine, which failed in two human trials in 2003, was successfully re-purposed as a "booster" vaccine for the RV144 study.
     
  • 50 percent is not out of our reach. In fact, the Thai study showed that the efficacy rate of the vaccines was more along the lines of 60 percent in the first year, waning progressively as time progressed. This suggests that additional inoculations or boosting strategies might provide greater and more durable protection.
     
  • We need to find ways to "limit the competition." Recent research has shown that competing antibodies may be at the heart of the RV505's failure. Genetic modelling suggests that the vaccines not only stimulated the production of immunoglobulin G (IgG) antibodies, as intended, but also prompted the rise in immunoglobulin A (IgA) antibodies, which dampened the protective effect. Finding them means to overcome or this competitive effect will likely be the biggest challenge moving forward.
     
  • It is likely we will not find one single vaccine. Most experts agree that it may take a combination approach to either effect HIV eradication or provide a therapeutic "cure." By combining traditional vaccine and immunologic approaches, many believe that we can corner HIV, both in its ability to infect and its ability to conceal itself from detection.

Is Vaccine Research Worth the Billions Being Spent?

At a time when HIV funds are either being shrunken or redirected, some have begun to question whether the incremental approach—gathering evidence slowly by trial and error—warrants the $8 billion already spent on vaccine research. Some believe it to be a waste of human and financial resources while others like Robert Gallo have argued that current vaccine models are not strong enough to warrant an incremental approach.

On the other hand, as we begin to understand more about cell-mediated immunity and the stimulation of broadly neutralizing antibodies, others believe that the knowledge can be readily applied other facets of HIV research.

In a 2013 interview with the Guardian newspaper, Françoise Barre-Sinoussi, credited as the co-discoverer of HIV, expressed confidence that a functional cure may well be in sight within "the next 30 years."

Whether the prediction raises expectations or dampens hope, it is clear that moving forward is the only real option. And that the only real failure is one from which we learn nothing.

Sources:

Office of Technology Assessment. "Review of the Public Health Service's Response to AIDS." Washington, D.C.: U.S. Congress; February 2005: p. 28. Library of Congress Catalog Card Number 85-600510 .

Rerks-Ngarm, S.; Pitisuttithum, P.; Nitayaphan, S.; et al. "Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand." New England Journal of Medicine. December 3, 2009; 361(23):2209-20.

National Institute of Allergy and Infectious Diseases (NIAID). "NIH Discontinues Immunizations in HIV Vaccine Study." Washington, D.C.: National Institutes of Health (NIH). April 25, 2013.

U.S. Military HIV Research Program (MHRP). "RV144 Follow-up Study RV305 Begins in Thailand." Walter Reed Medical Center, Washington, D.C.; Media Release: April 11, 2012.

International AIDS Vaccine Initiative (IAVI). "Progress on the Path Toward an AIDS Vaccine." New York, New York; Media Release: June 2012.

Tomaras, G. "E103 HIV-1 Vaccine Elicited IgA and IgG Antibody Specificities." Journal of Acquired Immune Deficiency Syndromes. April 2013; 62(1):52.

MacNeil, J.; Johnson, M.; Birx, D; and Traumont, E. "HIV Vaccine Trial Justified." Science. February 13, 2004: 303(5660):961.

Connor, S. "A cure for HIV is now a realistic possibility." The Independent. Published May 19, 2013.

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