This article originally appeared in HIV Treatment Update, a newsletter published by NAM between 1992 and 2013.
This article is more than 13 years old. Click here for more recent articles on this topic

There are two ultimate solutions to HIV: a cure and a vaccine. We cover research towards a cure in this issue. But how is the search for an HIV vaccine going? Gus Cairns reports.

When HIV was discovered in 1984, the then US Health Secretary Margaret Heckler forecast “a vaccine ready for testing in approximately two years.” Years later, we are still nowhere near. Why is it so hard?

Firstly, vaccines work by tricking the body into mounting the immune response it would against a disease. But HIV compromises the body’s natural immune response. An HIV vaccine would have to create a response not usually seen.

Glossary

efficacy

How well something works (in a research study). See also ‘effectiveness’.

immune response

The immune response is how your body recognises and defends itself against bacteria, viruses and substances that appear foreign and harmful, and even dysfunctional cells.

vector

A harmless virus or bacteria used as a vaccine carrier to deliver pieces of a disease-causing organism (such as HIV) into the body’s cells to stimulate a protective immune response.

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

cure

To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a person’s body, or permanently control the virus and render it unable to cause disease. A ‘sterilising’ cure would completely eliminate the virus. A ‘functional’ cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness. 

Secondly, HIV is tremendously genetically variable. A vaccine would have to generate a broad spectrum of responses; in some cases, the virus develops immunity to them.

Three different approaches

Researchers have tried different strategies. One uses a live attenuated vaccine – the basis of many successful vaccines. An actual virus, capable of ongoing reproduction but genetically modified to do no harm, is injected. In animal trials of a live attenuated version of HIV, however, some of the monkeys eventually developed AIDS, because the virus became harmful again.1 So this strategy was largely abandoned, though some researchers are still investigating it.2

The second strategy is to inject bits of the virus to generate an antibody response. Antibodies attach themselves to foreign invaders and either destroy them directly, stop them from infecting cells, or flag them for destruction. An effective response could completely protect people against infection. There are tantalising signs that anti-HIV antibodies could do this, but few have been found to have the potency and efficacy needed. We know such antibodies exist – we find rare ones in the blood of some people; when injected into others they block infection. But we don’t know how to persuade the body to make them continuously.3

The third idea is to use a mock virus – a vector. Researchers package up bits of HIV that generate an immune response and put them inside the shell of a different, harmless virus. This smuggles pieces of HIV into immune cells, hoping to generate a memory response and stimulate production of CD8 cells or cytotoxic T-lymphocytes (CTLs) that kill off HIV-infected cells. This type of vaccine would not necessarily stop infection, but could dampen down HIV replication and render infection harmless.4

Three pivotal trials

To prove a vaccine’s efficacy, it has to be given to thousands of people. This is partly because the majority would probably not have caught HIV anyway, and partly because we don’t have a reliable ‘surrogate marker’ – an immune response that tells us the vaccine is working. Because of this, and cost, there have been few large efficacy trials: only three have provided pivotal results.

The first was of a vaccine called AIDSVAX. This recruited 5417 volunteers identified as being ‘at risk’ of HIV. AIDSVAX was a generalised antibody vaccine. It found that the annual infection rate in vaccinated participants was only 2.7% lower than those receiving placebo, nowhere near significant.5A similar trial of a different AIDSVAX formulation in Thailand fared no better.6

The next big trial, STEP, used a CD8 vaccine in volunteers at high risk of HIV infection. Their ad5 vaccine consisted of pieces of HIV in the shell of an adenovirus – a type of cold virus.7

During the trial, immune responses thought to be protective were seen in volunteers. There was shock, then, when the trial was ended prematurely. The vaccine actually appeared to make some people more vulnerable to HIV.

A 48% higher rate of infection in vaccine recipients was not statistically significant. However, there was a significant difference in those with immunity to pre-existing adenovirus infections.8 It seems that the body ‘recognised’ the adenovirus in these people and the resulting inflammatory response rendered immune cells more vulnerable to infection.

Expectations were low, then, for the third trial, RV144. This was a huge trial in Thailand. Most volunteers were heterosexuals at relatively low risk of HIV. It was controversial because it used the AIDSVAX antibody vaccine, which many scientists considered useless, in combination with ALVAC, a vector vaccine based on canarypox virus.

It was another surprise, then, when it produced a positive result. The group that took at least one dose had 31% fewer infections than those receiving a placebo. This was just significantly significant: the ‘true’ difference in infection rate could have been between 1 and 52%.9

Furthermore, the protection seemed to be generated by cells that recognised AIDSVAX and produced antibodies to it – despite that failing in the original trial.10

The response generated did look weak. It did not seem to protect volunteers at high risk of HIV and it waned over time: if the study had stopped six months after the first dose, instead of continuing for 3.5 years, the protection rate would have been 60%.

After debate about a possible statistical fluke, most immunologists now accept that the RV144 vaccine did have a real effect – which might be improved. Two studies will start this year: one, RV152, giving ‘booster shots’ to people who received RV144. In another, yet to start, 125 recipients new to RV144 will get a double dose. A trial using a different vector is also planned.11

These will be small studies that can’t prove ‘real world’ efficacy. There are tentative plans for big efficacy trials, but there’s no widespread appetite for them, given that there is so much we don’t know about RV144.

Because we don’t know why some vaccines work and others don’t, time-consuming and expensive investigatory trials are still needed. A paper from the International AIDS Vaccine Initiative12 revealed it takes US$500 million to develop a typical vaccine, but the AIDSVAX and RV144 trials alone cost $235 million.

There is pressure from funders to speed things up. Bill Gates, a major funder of HIV vaccine research, has demanded that researchers “minimise the length of trials and the time between trials”.

One strategy being considered is ‘adaptive trials’: the aims and strategy of your trial change as you go along. You build in criteria for stopping fast if the vaccine looks harmful, ineffective, or even highly effective, and if you anticipated the vaccine would do one thing, but it does another, you change its ‘primary endpoint’, the main thing it measures. 

This is controversial because of the danger of biased results: searching long enough for evidence will probably find some. There are ethical debates too - is it wrong to keep giving a placebo if your vaccine may be working?

The RV144 result has regenerated a degree of low-level excitement in HIV vaccine researchers. We still don’t know the way to an HIV vaccine – but there are signs there is one.

References
  1. Hofmann-Lehmann R et al. Live-attenuated, nef-deleted SIV is pathogenic in most adult macaques after prolonged observation. AIDS 24:17(2):157-66, 2003.
  2. Berkhout B Evolution of live-attenuated HIV vaccines. BioPharm International Supplements 24:s4-s8, 2011.
  3. For more on broadly neutralising antibodies, see IAVI Report Understanding advances in the search for antibodies against HIV. http://tinyurl.com/5wzj49d Date accessed: 25 February 2011.
  4. For more on cellular immunity, see IAVI Report Understanding cellular immune responses. http://tinyurl.com/6xqxe9d Date accessed: 25 February 2011.
  5. Flynn NM et al. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV- 1 infection. J Infect Dis, 191, 654-665, 2005.
  6. Pitisuttithum P et al. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV- 1 vaccine trial among injection drug users in Bangkok, Thailand. J Infect Dis, 194, 1661-1671, 2006.
  7. Robertson M, Buchbinder S et al. Efficacy results from the STEP Study (Merck V520 protocol 023/HVTN 502): a phase II test-of-concept trial of the MRKad5 HIV-1 gag/pol/nef trivalent vaccine. 15th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 88LB, 2008.
  8. Perreau M et al. Activation of a dendritic cell-T-cell axis by Ad5 immune complexes creates an improved environment for replication of HIV in T cells. J Exp Med 205(12): 2717-25, 2008.
  9. Rerks-Ngarm S et al. Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand. N Engl J Med 361(23):2209-2220, 2009.
  10. US Military HIV Research Program RV144: Preliminary Laboratory Project Briefing. 2010. See www.hivresearch.org/media/pnc/0/media.410.pdf.
  11. For more see Vaccine Briefs Researchers Unveil Plans for Follow-up Trials to RV144. IAVI Report 14(3), 2010.  See http://tinyurl.com/69lu57m.
  12. McEnery R Investing in Surprise. IAVI Report 14(2), 2010. See http://tinyurl.com/4oujl4u