Vaccines

Why the need for a vaccine?
Many experts believe that an effective preventive vaccine is the only way to eliminate HIV.¹ The hope is that by using a vaccine, HIV can be eliminated in the same way that smallpox, which is also a viral disease, was eradicated. Unfortunately, with HIV, developing a vaccine is no easy task, and there are many challenges involved.

However, even a partially effective vaccine would be of great benefit to people infected with the virus, and to society as a whole by reducing transmission.

How do vaccines work?
A vaccine is a substance that gives rise to specific responses in the immune system. The immune system protects our body against harmful invaders like bacteria, and viruses such as HIV. It can do this through:

• antibodies; or
• cellular immune responses - via cytotoxic (‘cell-killing’) killer T-cells; or
• both of the above.

The immune responses may protect against disease in three different ways:²

• Preventing infection
  A vaccine might prevent a person becoming infected with HIV. It could do this by preventing the virus from infecting any cells. Enough antibodies would need to be produced to ‘neutralise’ the virus. Alternatively, an early HIV infection might be cut short by neutralisation of the virus and causing the death of already infected cells. This may require a cellular immune response as well as antibodies.
• Delaying illness (therapeutic vaccines)
  Secondly, a vaccine might delay or prevent the progression of illness, despite HIV infection. This effect is likely to depend on a cellular immune response directed at HIV-infected cells. Studies using animals show that this is possible.
• Blocking transmission
  Thirdly, a vaccine might reduce the chance of transmission of HIV to others, for example from a mother to her baby, or sexual transmission.

How do researchers go about making a vaccine?
Usually, vaccines are made by using:

• a weakened strain of the virus (‘live-attenuated vaccine’); or
• killed viruses; or
• genetically engineered proteins (or ’recombinant’ proteins) from the surface of viruses.³

These are used to inoculate against diseases such as measles, mumps and rubella (MMR vaccine), poliomyelitis, influenza and hepatitis B. However, when it comes to HIV, live-attenuated vaccines and killed viruses are considered too dangerous, so researchers are looking at the use of ’recombinant’ proteins, a safer option for making HIV vaccines.

‘Recombinant subunit’ vaccines, based on a protein from the HIV ‘s outer envelope, called gp120 were the subject of the first full-scale HIV vaccine trials to be completed. Unfortunately the trials of vaccines with this relatively simple approach were not successful, since they showed no significant difference between rates of HIV infection amongst people who received the vaccine, compared to those who did not.

A more promising approach is to present multiple HIV proteins in ways that stimulate cellular immune responses with so-called ‘killer T-cells’ against cells that have already been infected with HIV.

Another way is based on modifying HIV’s envelope proteins or mimicking small regions of the virus’s surface, with a view to creating stronger and more effective antibody responses than occur naturally.⁴

What is happening in South Africa?
The biggest African commitment to vaccine development has been made by the South African government, which is backing the South African AIDS Vaccine Initiative (SAAVI), led by the South African Medical Research Council (SAMRC), providing a framework for a number of international partnerships.⁵

SAAVI’s goal is to develop an effective, affordable HIV vaccine that works for the South African population. It is trying to do this both through a South Africa research and development programme aimed at developing new test vaccines and also by testing promising-looking test vaccines developed elsewhere in the world in clinical trials.

It is a comprehensive biotechnology programme with activities ranging from basic science, to running clinical trials, to socio-behavioural research, to ethics and human rights research and community involvement activities. SAAVI funds over 200 researchers and others at centres of excellence across the country.

It was established in 1999 and receives its funding from two government departments, Eskom, the European Union and other local and international partners. There are currently six clinical trials running in the country. In February 2007 an announcement⁶ was made by SAAVI that the first large-scale test of concept HIV vaccine trial in South Africa would shortly start recruitmen of volunteers.

Where do we stand now?
Despite 20 years of research there is still no vaccine that works in humans to prevent HIV infection. Developing a vaccine against AIDS has proved to be a lot more complex than anyone thought it would be. Part of the problem is that the virus constantly mutates (changes) so that the immune system no longer recognises it as such and HIV attacks exactly the immune system cells that are supposed to protect us against viruses.
Despite the problems, though, researchers in the AIDS vaccine field have been encouraged by recent developments. A leading researcher said that 2006 has been “a vintage year for vaccine development”.⁷ Three promising vaccines are producing impressive immune responses. By 2008 or 2009 we should know whether one of these, the Merck adenovirus-based HIV vaccine, has some protective effect against HIV transmission.

The ‘take home’ message for vaccines is that many challenges remain and it will still be a number of years before an HIV vaccine is released, but there is still hope for the future. In the mean time, scientists are looking at other promising ways to limit HIV transmission, such as microbicides.

Microbicides

Why microbicides?
Vaccines would be the ideal solution to the control of HIV infection. However, as seen above, in spite of much effort and investment there is currently no proven vaccine against HIV.

Because there is no vaccine available yet, we have to focus on other methods to prevent HIV being transmitted. Condoms for males have been found to be highly effective,⁸ but condom use is almost exclusively under the control of the male partner. In many societies women simply cannot insist that their partners use condoms, and they are vulnerable to abuse and exploitation.

A method which could be controlled by women to prevent or reduce HIV risk is highly desirable, since sex education could then be used to promote mechanisms for both males and females. Also, if used together with a condom or other barrier method, the effect on the reduction of HIV infection could be much greater than with any one method used on its own. Microbicides could have a great impact on public health: it has been estimated that even if a microbicide is only 60% effective, it could avert 2.5 million new infections over the next 10 years.⁹

What are microbicides?
Microbicides are chemical agents like gels or creams that are applied directly by women within the vagina, in order to prevent infection by HIV and potentially also by some other viruses, and sexually transmitted pathogens (disease-producing micro-organisms). The original type of microbicide was designed to be inserted before each act of sexual intercourse and could also be contraceptive, although most current microbicides are not.¹⁰

Vaginal rings containing the microbicide are also being developed. These would be inserted in the vagina and this would allow the microbicide to be released slowly over weeks or months. In this way, adherence would not be a problem since the woman would not have to use the microbicide before each act of intercourse.

What would constitute a successful microbicide?
To be successful, microbicides will need to be shown to be effective in phase III trials¹¹, and will need to be non-toxic and well tolerated, odourless and colourless, easily administered, and cheap to manufacture.

How do microbicides work?
There are three main types or ‘generations’ of microbicides, where scientists have used three different approaches:

• Surfactants. These act in the same way as detergents, and act by destroying the HIV envelope (outer layer). This damages the HIV virus and renders it incapable of causing an infection. Unfortunately, the surfactants can also damage the epithelium, the protective layer of cells lining the vagina and rectum, so scientists are focusing on using low concentrations of the surfactants in the microbicide products.
• Blocking entry of HIV into the healthy cells of the vagina (the ‘host’ cells). It does this by preventing the attachment of the HIV to the host cell’s receptor, or docking protein. The attachment to the receptor is similar to a key fitting into a lock, and is the first step necessary if the HIV is to enter the cell. An example of this type of microbicide is a product called carrageenan, a seaweed derivative. A trial in South Africa has enrolled over 6 000 women to test the product.
• Antiretrovirals
  Tenofovir is an antiretroviral drug (ARV) used as a medicine taken orally to treat HIV infection. Researchers found that if they gave macaque monkeys this drug before trying to infect them with simian immunodeficiency virus - the monkey equivalent of HIV in humans - it seemed that they were protected against infection by the virus. The researchers decided that this principle could also be used in microbicides, so they have developed a gel containing tenofovir, to prevent HIV infection in women.

It is not clear yet, which of these mechanisms will prove to be most effective, as trials are still in progress, but eventually, women should be able to choose from different microbicides according to their specific needs. For example, microbicides tested could be contraceptive or non-contraceptive. This will give women the choice to conceive without the fear of HIV infection.

Challenges with Phase III Trials of Vaginal Microbicides
In order to test how well the microbicides work, they must be tested in a group of women where the incidence of HIV infection, in other words new infections, is relatively high. But at the same time, the women should be counselled, screened and treated for sexually transmitted infections, and given condoms and health education. The women need to use the microbicides ‘to protect every risky act of intercourse’, but as with male condoms, adherence is unlikely to be complete and may reduce over time. This means that they may start off well, but as time goes by they may forget to use it more and more.

Another problem is that women may become infected with HIV through frequent anal intercourse or the use of non-sterile needles. This would reduce the effect of the microbicides.

These trials are ‘financially challenging’, and so need support from charities and the public sector. Because of the very high costs, it is likely that phase III trials will be the major rate-limiting step to new product development and testing.

In additon, for various reasons, trials are not always successful, despite the fact that all possible care is taken. For example, in February this year it was announced that a Phase III trial of cellulose sulfate microbicide for HIV prevention has been closed. However it should be noted that this is just one of several trials, and other possible microbicidal substances are still being tested.

Several phase III trials of these other candidate microbicides are currently in progress. According to some optimistic projections, a microbicide may be available for use by 2010.

In conclusion, vaccines are a long term goal, but microbicides seem to be within reach in the near future. Methods like these, which can help prevent HIV infection, are particularly relevant in a country like South Africa, where the prevalence rate in 2005 was estimated to be 18.8%.¹²

References

1. http://www.aidsmap.com/en/docs/6FAAAB99-6C46-4A35-9392-A8ABC5AA9A5A.asp
2. http://www.aidsmap.com/en/docs/868ABF57-E501-445F-A2B2-84483E7201A3.asp
3. Aids GUIDE2006: 142.
4. http://www.aidsmap.com/en/docs/E28BD009-4B6E-45CF-918F-0E2C34664070.asp
5. http://www.aidsmap.com/en/docs/3D77110B-4D23-423A-9CFA-93B8278F16FC.asp
6. See SAAVI press release at http://www.saavi.org.za/1press2007.htm
7. http://www.aidsmap.com/en/news/4AF3F36A-6A14-4C0A-BB4F-1ADE008F80E7.asp
8. Weller, S., Davis, K. 2002. Condom effectiveness in reducing heterosexual HIV transmission. Cochrane Database Syst Rev 2002: CD003255.
9. Public Health Working Group: model projects, 2002.
10. Weber, J., Desai, K., Darbyshire, J. The development of vaginal microbicides for the prevention of HIV transmission. PloS Medicine (www.plosmedicine.org) May 2005. 2(5) e142: 0392-0395
11. Phase III trials  use large numbers of subjects to test whether a medication works or not.
12. http://www.globalhealthfacts.org/country_pf.jsp?c=197&cat=1

Authors: Mary Mattheyse, AfroAIDSinfo and Michelle Galloway, SAAVI