AIDS Vaccines and Microbicides

Why do we need AIDS vaccines and microbicides?

AIDS vaccines and microbicides don’t yet exist but they are undergoing research and development. Vaccines and microbicides have a number of key advantages over today’s HIV prevention options.

Even a partially effective vaccine or microbicide could save many millions of lives. Experts have calculated that a vaccine that is 50% effective, given to just 30% of the population could reduce the number of HIV infections in the developing world by more than half over 15 years. More effective vaccines could cut the infection rate by more than 80%.¹

“Developing a safe and effective vaccine against HIV is critical to our efforts to control the devastating pandemic of HIV and AIDS” - Dr Anthony S. Fauci, Director of NIAID -²

So what is a vaccine?

A vaccine is something that teaches the body to recognise and defend itself against viruses or bacteria that cause disease. Vaccines either help to prevent infection, or help to prevent or delay illness in people who are already infected. A vaccine is not the same thing as a cure for AIDS.

Effective vaccines have already been developed for some diseases, such as smallpox, polio and tetanus, and these have saved millions of lives. But there is still no vaccine against HIV, the virus that causes AIDS.

And what is a microbicide?

A microbicide is something designed to destroy microbes (bacteria and viruses) or to reduce their ability to establish an infection. A microbicide for preventing HIV infection would be applied to the vagina or rectum to prevent the virus being passed on during sex.

It is quite possible that an HIV microbicide could be available sooner than an AIDS vaccine.

What are the advantages of AIDS vaccines and microbicides?

An AIDS vaccine would have many advantages over current options for preventing HIV infection. In particular, the protection offered by a vaccine during sex would not depend on the consent of both partners (unlike condom use), and would not require behaviour change (unlike abstinence). A vaccine would be invaluable for couples wishing to conceive a child while minimising the risk of HIV transmission.

Children could be given a vaccine before ever being exposed to the virus, and ideally this would protect them from all routes of HIV transmission, including unsafe injections. Vaccinating large numbers of people would probably require relatively little equipment and expertise, and would be much simpler and cheaper than providing antiretroviral treatment for those already infected.

A microbicide would share many of the advantages of a vaccine. It would be especially useful for women unable to insist on using condoms, who might be able to use a microbicide without their partners knowing. However, a microbicide would not be able to prevent all forms of HIV transmission, and would require regular reapplication. Unlike vaccines, an effective microbicide must be made into a commodity that people will want to use regularly, such as a cream, gel or vaginal ring.

How might an AIDS vaccine work?

This X-ray of an antibody (green) in contact with an HIV

protein (yellow and red) reveals a possible target for

AIDS vaccine developers

An AIDS vaccine could be effective in either of two ways. A “preventive” vaccine would stop HIV infection occurring altogether, whereas a “therapeutic” vaccine would not stop infection, but would prevent or delay illness in people who do become infected, and might also reduce the risk of them transmitting the virus to other people. Although a preventive vaccine would be ideal, a therapeutic vaccine would also be highly beneficial.

The basic idea behind all AIDS vaccines is to encourage the human immune system to fight HIV. The immune system works using a combination of cells and chemicals called antibodies. Early vaccine research focused on teaching the immune system to produce antibodies that would block HIV entering human cells. However, products designed to work this way failed in clinical trials because the antibodies worked only against lab-cultured HIV, not against the wild strains of the virus.

Most recent research has focused on encouraging the immune system to produce cells to fight HIV. Nevertheless, many scientists believe such “cell-mediated” approaches will not be very effective on their own, even as therapeutic vaccines. It seems likely that a really effective vaccine will have to take a two-pronged approach involving both cells and antibodies.

A vaccine could consist of whole HIV that has been modified to make it harmless (though this raises safety issues), or it could be based on parts of the virus, such as proteins or genes. One way to deliver parts of HIV is to put them inside a “vector” that is harmless to humans, such as the canarypox virus.

Why is it difficult to develop an AIDS vaccine?

Developing a vaccine against HIV is a very difficult challenge for scientists. There are many reasons for this, including:

Nobody has ever recovered from HIV infection, so there is no natural mechanism to imitate
HIV destroys the immune system cells that are meant to fight against it
Soon after infection, HIV inserts its genetic material into human cells, where it remains hidden from the immune system
HIV occurs in several subtypes, each of which is very different from the others
Even within each subtype, HIV is highly variable and constantly changing
There are no good animal models to use in experiments

Can these difficulties be overcome?

There are reasons to be optimistic about the search for an AIDS vaccine, despite the slow progress so far. Vaccines against other diseases took many decades to develop, whereas HIV was only discovered in the mid 1980s. It is therefore much too early to give up hope, especially given the current speed of scientific progress. In the past, some experts doubted the possibility of an effective polio vaccine, yet today polio is close to being eradicated thanks to successful vaccination programmes.

One particular reason for remaining hopeful is that most people remain healthy for several years after becoming infected with HIV, and a small minority have survived as long as 20 years without developing AIDS, even though they never entirely rid themselves of the virus. Also it appears that a few people have some kind of natural resistance to HIV infection, meaning they never become infected despite repeated exposure to the virus. These facts suggest that the immune system can be quite effective at controlling HIV.

How might an HIV microbicide work?

A microbicide could work in at least four different ways:

Kill or inactivate HIV
Stop the virus entering human cells
Enhance the body’s normal defence mechanisms against HIV
Inhibit HIV replication

It is possible that a microbicide could work in much the same way as a vaccine, so research in one area could benefit the other. Alternatively, a microbicide could work in a similar way to today’s antiretroviral drugs, or it could act like a detergent.

What are the challenges in developing HIV microbicides?

There are many chemicals that kill HIV, including undiluted household bleach. But what is needed for a microbicide is something that works against HIV without causing discomfort or irritation. For example, when researchers investigated using the spermicide Nonoxynol-9 as an HIV microbicide they were surprised to find it actually increased the rate of transmission, probably because it caused vaginal lesions and inflammation, which made it easier for HIV to establish an infection, even though Nonoxynol-9 killed the virus in lab tests.³ ⁴

For a microbicide to become popular, researchers must develop not only the active ingredient but also a delivery method that is safe, effective, acceptable and affordable. Ideally this would provide protection for several days or even weeks at a time.

Another major issue is how a microbicide affects sperm. To reach all those in need, scientists will have to develop both contraceptive and non-contraceptive microbicides.

Who is supporting research and development?

Lab technician working on AIDS research

In 2006, the public, philanthropic and private sectors invested around $933 million in preventive vaccine research and development, which is about 1% of all funds invested in developing health products. Around 83% of this money comes from the public sector - primarily the US government. The commercial sector accounts for 8%, and philanthropies for another 8%. Public sector investment more than doubled between 2000 and 2005, though funding from the commercial sector has not kept pace.⁵ ⁶

In 2006 around $222 million was invested in microbicide research and development - up by 35% on the previous year. About 86% of this money came from the public sector, while commercial companies accounted for around 2% (only $4.5 million).⁷ At present no major pharmaceutical firm is investing significant amounts of its own money in microbicide research because it is complex and the market is uncertain. As Professor Jonathon Weber has stated:

“[Microbicides] are perceived as drugs for Africa, and no one makes money from Africa”⁸

The quest for a vaccine is aided by the not-for-profit International AIDS Vaccine Initiative (IAVI), which helps to support and coordinate vaccine research, development, policy and advocacy around the world. In addition an alliance of organisations called the Global HIV/AIDS Vaccine Enterprise exists to coordinate research and promote scientific cooperation and collaboration. The International Partnership for Microbicides and the Alliance for Microbicide Development work to accelerate the search for microbicides.

How are the candidates tested?

Any potential vaccine or microbicide must pass through three phases of clinical trials before being judged safe and effective. The first phase usually lasts from twelve to eighteen months, whereas the last phase can take three or four years to complete. In most cases volunteers must be HIV-negative at the start of the trial, though it is important also to test safety in those who are already infected. Some therapeutic vaccine candidates may be tested on HIV-positive people to see if they can delay disease progression.

Phase I involves a small number of volunteers to test the safety of various doses
Phase II involves hundreds of volunteers to further assess safety and, in some cases, positive responses
Phase III involves thousands of volunteers to test safety and effectiveness

A recent innovation is the Phase IIb trial, a larger variant of the Phase II trial that provides some indication of effectiveness.

Trials of AIDS vaccines and microbicides are made more difficult by the ethical obligation to provide condoms and prevention counselling to all those who take part. Providing such services lowers the overall rate of HIV transmission, which increases the number of volunteers required to produce a significant result.

What vaccine trials have already taken place?

The first AIDS vaccine candidate to undergo Phase III trials was called AIDSVAX. Two separate studies were conducted. One had around 5,400 participants - mostly gay American men - while the other involved around 2,500 injecting drug users in Thailand. The vaccine, known as AIDSVAX, was made from a single HIV protein and was meant to stimulate a protective antibody response. The trials began in 1998 and 1999 respectively, and ended in 2003. No beneficial effect was found in either population group.⁹

There is some concern that slightly more HIV infections occurred among people who received the Merck vaccine than among those who took a placebo

Two Phase IIb trials of a vaccine candidate created by the pharmaceutical company Merck were halted in September 2007. The studies - known as STEP and Phambili - had been expected to produce their first results by 2010. They were stopped when researchers found that people receiving the vaccine were no less likely to become infected with HIV than those taking a placebo. The STEP trial had started in 2004 in the USA, Canada, Australia, Peru and the Caribbean; the Phambili trial had begun in January 2007 in South Africa.¹⁰ ¹¹

There is some concern that slightly more HIV infections occurred among people who received the Merck vaccine than among those who took a placebo. The vaccine was delivered using adenovirus type 5, which causes the common cold. It has been suggested that the vaccine may have provoked a different immune response among people who already had some immunity to the adenovirus strain, and that this may have made them more susceptible to HIV infection. This hypothesis - which is supported by laboratory evidence¹² - raises questions about the use of adenovirus in future vaccines.¹³ It has also been noticed that uncircumcised men were four times more likely to become infected with HIV if they received the vaccine than if they received the placebo; the reasons for this pattern are unknown.¹⁴

Leading vaccine researcher Dr. Gary Nabel has described the results of the Merck vaccine trial as “a big blow to the field”. Several other vaccine studies have been delayed to ensure that mistakes are not repeated.¹⁵ ¹⁶ Nevertheless Dr. Seth Berkley, President and CEO of the International AIDS Vaccine Initiative, has stressed that the outcomes are not all negative:

“Though the Merck candidate failed, the trial did not. The contribution of the volunteers was not in vain. As a result of their dedication, the field will have new data that will inform future vaccine design, help with the prioritization of candidates in the pipeline and guide decisions on how to best proceed with ongoing and upcoming trials.”¹⁷

What vaccine trials are now underway?

As of August 2007, thirty-six human trials of AIDS vaccine candidates were taking place around the world. This number included twenty-seven Phase I trials; eight Phase I/II, Phase II or Phase IIb trials; and one Phase III trial.¹⁸ Many more products were still at the development stage. It is unclear how many human trials have been delayed or suspended following the failure of the Merck vaccine candidate.

The Phase III trial, which has recruited 16,000 young adults in Thailand, is of a canarypox-based vaccine called ALVAC combined with an AIDSVAX booster. ALVAC is designed to stimulate a cellular response to HIV, while AIDSVAX promotes the production of antibodies.

AIDSVAX failed in previous Phase III trials. The hope is that combining it with ALVAC will produce better results. The study is due to end in late 2009, but the first preliminary results may be published in 2008.¹⁹

How many microbicide trials are under way?

Eight HIV microbicide candidates were undergoing trials in mid-February 2008.²⁰

Three microbicide candidates are in Phase IIb or Phase III trials to test their effectiveness:

BufferGel, which maintains acidity in the vagina
Tenofovir gel, which is based on an antiretroviral drug
PRO 2000, a type of entry inhibitor

Which microbicide trials have recently ended?

In August 2006, Family Health International decided to halt a Phase III trial of a surfactant called SAVVY after preliminary results showed no evidence of a protective effect. The organisation has no plans to further investigate this product.²¹

Two Phase III trials of an entry inhibitor called cellulose sulphate (also known as Ushercell) were halted in January 2007 after some sites recorded a higher HIV infection rate among women who used the gel, compared to those in the placebo group. This result led to speculation that the gel may have increased the risk of HIV transmission. Later analysis indicated that the higher infection rate may have been due to chance.²²

In February 2008, researchers announced the results of a Phase III trial of Carraguard, an entry inhibitor based on carrageenan, which is derived from seaweed. The product - the first ever to complete Phase III testing - was shown to be safe, but had no significant effect on HIV transmission.²³ ²⁴

Also in February 2008, it was decided that the largest PRO 2000 trial should stop testing a higher strength version of the product because it was unlikely to be beneficial. A weaker version was investigated,²⁵ but in 2009 the results that were presented were not statistically significant. Therefore the effectiveness of PRO 2000 is not yet known. ²⁶

How soon could we have an effective vaccine?

In 1984, at the press conference arranged to announce the discovery of HIV, the US Health and Human Services Secretary Margaret Heckler said she hoped a vaccine against AIDS would be ready for testing in about two years.²⁷

Unfortunately, the problem has turned out to be much more challenging than Secretary Heckler expected. Today’s researchers agree that the quest for an AIDS vaccine still has a long way to go. It is unlikely that any effective product will be available before 2015 at the earliest. It’s even possible that the search could last decades.

The failure of the STEP trial in 2007 in particular has led some scientists to question whether the current approach to AIDS vaccine development has much chance of success, given that it favours products that work in a similar way to the failed Merck candidate. Critics suggest that an entirely different strategy may be required, based on better understanding of HIV's interactions with the immune system.²⁸

“The path forward is not clear. I think there is agreement on that. Anybody who talks about a timeline for a vaccine is being silly and uninformed. It will require an incremental process of knowledge, and experimentation, and testing of ideas.” - Professor John Mellors -²⁹

The news media regularly announce a new “breakthrough” in AIDS vaccine research. However, most of these stories refer to products in Phase I or Phase II trials, where there has been no evidence of the product actually working in humans. Such stories are realistically talking only about potential breakthroughs.

Few if any vaccines are 100% effective. Most probably the first AIDS vaccines to succeed in trials will offer only partial protection, and these may need to be improved or combined with other products before being suitable for widespread use. Vaccine development is likely to proceed by small, incremental steps; we are unlikely to see any immediate “miracle breakthrough”.

What about a microbicide?

It is quite possible that an effective microbicide could be available sooner than a vaccine – even as early as 2010 if one of the leading candidates succeeds in trials. Any successful product would have to undergo review and licensing by regulatory agencies before becoming available to the public.

Reaching people in need

If trials conclusively find a particular vaccine or microbicide to be safe and effective then the next challenge is to help people access it. This involves working out the best formulation and dosage; finding a suitable delivery method; and distributing the product. In addition both governments and individuals will need to be convinced that the product is worth investing in. The process of getting a vaccine or microbicide to all the hundreds of millions of people in need could take many years.

An important consideration is whether a vaccine or microbicide could undermine the popularity of existing HIV prevention methods, such as condoms. If a product is only partially effective (as is almost inevitable) then experts will have to weigh up the potential risks and benefits very carefully before considering distribution. Upon release of any product, awareness-raising and prevention efforts will need to be redoubled to counter the risk of complacency.

“A future vaccine will not be a ‘magic bullet’. But future vaccination against HIV, applied alongside prevention measures based on safer behaviour and STI control, holds out realistic hope for ending the AIDS epidemic.” - UNAIDS -³⁰

Conclusion

It is very unlikely that HIV and AIDS will ever be eradicated without new scientific developments. Eventually, unless great progress is made in prevention, the number of people living with HIV will outstrip the resources available for treatment. The search for effective vaccines and microbicides must therefore be one of the very highest priorities for scientific research.

However, it is not realistic to expect such research to produce a major breakthrough for some time yet, and we should be wary of news stories suggesting otherwise. Any new discovery needs to undergo trials lasting years, and must then be distributed around the world before we will see its full benefits.

In the mean time, the world must continue to scale-up existing prevention and HIV treatment programmes. Millions of lives can be saved using the knowledge and tools already at our disposal, provided the world commits itself wholeheartedly to the cause.

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