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Vaccine technologies
   Last updated: 03.11.04
 
The goal in current preventive vaccine research is to delay HIV disease progression, or to reduce HIV transmission. While a vaccine which prevents infection directly and completely would be ideal, many researchers believe it will be hard to achieve this due to the integration of HIV's genetic material within the nucleus of human cells. This allows HIV to create a long-lived reservoir of infection that is difficult to detect.

Researchers have been looking for an HIV vaccine that stimulates HIV-specific antibodies to block HIV from entering cells and to eliminate infected T-cells. There is also an interest in looking at specific immune responses in the mucosal surfaces which are likely to be critical for preventing sexual transmission.

Types of vaccines
Researchers have explored a number of strategies which they hope will produce protective immune responses.

Types of vaccines which have been investigated to date include:

  • Live attenuated vaccines. These are defective viruses that are harmless to people, but which stimulate the body to produce an immune response. Research to date in monkeys indicates that attenuated viruses can cause AIDS, albeit more slowly than the normal virus. Clearly, this would be unacceptable for human use.

  • Inactivated or 'killed' vaccines. There may have been more research on these than has been reported, but there have been no claims of a significant level of success.

  • Recombinant sub-unit envelope vaccines. These seek to stimulate antibodies to HIV by mimicking proteins on the surface of HIV. Sub-unit vaccines researched to date have been strain-specific and have produced poor antibody responses. However, recent research has opened up new areas of envelope vaccine research and there are now hopes for envelope vaccines which would be effective against a range of HIV clades and strains. Naturally-occurring antibodies of this kind are feeble compared to antibodies against many other viruses, but there is still experimental evidence that some combinations of such antibodies can protect monkeys against transmission of simian/human immunodeficiency viruses (SHIVs).

  • Recombinant vectored vaccines. These incorporate fragments of HIV into established vaccines made from live but harmless viruses, such as the canarypox viruses or adenovirus. Vector vaccines have been shown to produce HIV-specific cytotoxic T-cell responses in animals and humans. In mice and monkeys, DNA vaccine priming can enhance responses to these vectors, but this effect has not so far been seen in humans. Adenovirus vectors appear to be among the best of those tested so far, but the first and most widely used strain, Ad5, has problems on account of widespread natural immunity to this common virus.

  • DNA vaccines and replicons. This approach involves injecting genetic sequences from HIV into people to induce the expression of HIV proteins by human cells. In the case of replicons, these sequences are wrapped in the outer coat of an unrelated virus. DNA vaccines work very well in mice, less well in monkeys, and rarely in humans. The main problem seems to be one of delivering a sufficient dose, with physical limits to the amount of DNA that can be injected at any one time. New methods to ‘package’ and deliver the DNA may eventually overcome these problems. Replicons, using viral coat proteins to deliver DNA or RNA to particular types of cell, may be the best way to solve them.

  • Combination or 'prime and boost' vaccines. These are strategies for combining two or more different vaccines to broaden or intensify immune responses. Examples include a vector virus to prime a T-cell response with a subunit booster to produce antibodies, or two different vector viruses expressing the same gene sequence. It is possible that two different vaccines could be given at the same time, where one acts more rapidly than the other, giving a 'prime-boost' effect from a single dose.

An important recent development in vaccine design is the use of synthetic HIV genes with 'optimised sequences' to maximise their expression in the human cell. This technique produces enhanced immune responses in animals and several vaccines using this technique are now in clinical trials.

To date, over 40 different HIV vaccines have been tested in several thousand volunteers. Most of this research has consisted of early safety and efficacy studies of recombinant proteins, produced in a variety of different systems. Researchers have looked for any detrimental effects of vaccines as well as any HIV-specific immune responses that may have been induced. There has been some encouraging evidence of immune responses in people, although it is unclear whether these responses would prevent HIV infection. These vaccine strategies are discussed in more detail in the following sections.

Human vaccine trials
A number of vaccine trials are currently underway:


  • The next most advanced studies have focussed on a series of canarypox-based vaccines made by Aventis Pasteur. These vaccines are still being studied in one large trial in Thailand as 'primers' with VaxGen's AIDSVAX as a 'booster'. In another trial, they are to be combined with lipopeptides chosen to enhance cellular immune responses. They are also being studied as potential therapeutic vaccines. Animal studies recently suggested they could be effective boosters for the adenovirus-based vaccine developed by Merck & Co. Unfortunately, when this was tested in a clinical trial, it emerged they were no better than repeated use of adenovirus for this purpose when given to human volunteers.

  • The International AIDS Vaccine Initiative (IAVI), in partnership with the Medical Research Council, the University of Nairobi, the Uganda Virus Research Institute and other African agencies is conducting clinical trials of a prime-boost vaccine based on synthetic subtype A gag gene sequences. This is discussed in Recombinant sub-unit vaccines .

Several other studies of prime and boost vaccines are planned. For example, the United States National Institutes of Health is sponsoring an American-South African vaccine partnership, using a replicon vaccine designed by a company called AlphaVax. This vaccine is produced by wrapping a subtype C gene sequence inside the coat of a virus called Venezuelan equine encephalitis (VEE). This was originally promoted by IAVI, and recently entered phase I clinical trials in both countries.

Countries with an active interest in vaccine development which have already held clinical trials now include Brazil, Cuba, France and Uganda in addition to those already mentioned. There are trial sites or international collaborative vaccine programmes now being established in China, Ivory Coast, Haiti, India, Japan, Nigeria, Peru, Rwanda, Switzerland and Trinidad among other countries.

Animal models
Most vaccine research involves animals, since this allows direct testing of vaccines, by 'challenging' immunised animals with known quantities of viruses. This can give clear and rapid answers to questions about vaccine effectiveness, but the relevance of these findings to humans still has to be established.

There is no ideal animal model for AIDS vaccine work, although a variety of options exist. Vaccine research is done using mice, rabbits or other small animals, usually to see if a vaccine can induce immune responses.

Some researchers have used severe combined immune deficiency (scid) mice in vaccine research. These mice lack a functional immune system, so human tissues can be transplanted into them without rejection. By transplanting humane immune system cells into them, they can act as a model for the human immune system. However, while these scid-hu mice can be infected with HIV-1, they are a long way from having fully functioning human immune systems and are not thought to provide a reliable guide to what will work as a vaccine in humans.

Monkey models
Before they are put forward for clinical trials in humans, most potential HIV vaccines are evaluated in monkeys. This is the reason for the large number of references that describe experiments with simian immunodeficiency virus (SIV), simian/human immunodeficiency virus (SHIV) and HIV in non-human primates.

HIV-1 and HIV-2 are members of a larger family of viruses known as SIVs. These are found in wild populations of African monkeys and apes. Understanding these viruses in monkeys and apes can help towards understanding HIV in humans and may also be of veterinary value for monkeys in captivity.

Typically, these viruses do not cause illness in the wild animals they infect, but may do so when transferred from one species to another. Evidence has emerged that HIV-1 is descended from an SIV native to one subspecies of chimpanzee (Pan troglodytes troglodytes), found in west central Africa. This may help explain the observation that chimpanzees generally do not become ill when infected with HIV-1. In turn, there is further evidence that the chimpanzee virus itself has evolved from one or more ancestral viruses present in some of the monkeys that chimpanzees hunt and eat.

Although rarely used nowadays, there are serious ethical and practical problems with using chimpanzees in HIV research. Furthermore, there are now real doubts about the relevance to humans of protection seen in chimpanzees against a virus from which they are naturally protected. Similarly, while some laboratory-adapted strains of HIV-1 are able to infect pigtail macaques, the fact that the monkeys do not become ill has led most researchers to consider evidence of protection in that model to be weaker than where SIV strains do cause illness.

To overcome the limited host-range of HIV-1, hybrid viruses have been developed, called SHIVs, some of which cause illness in the monkeys they infect. These combine elements of HIV-1 (typically the envelope proteins) with an SIV to allow direct testing of HIV vaccines, provided these are based on the HIV elements included in the SHIV. SHIVs may therefore be of limited use in testing vaccines that aim to create cellular immunity against the non-envelope proteins of HIV.

An additional problem with the most widely used strain of SHIV, known as 89.6P, is that it includes a form of the HIV envelope protein adapted to infect CD4 T-cells, known as an 'X4 virus' after the CRCX4 co-receptor it uses to enter those cells.

Unfortunately, when people are exposed to HIV, the first strains to be established in the body are those which are adapted to infect macrophages and use the CCR5 co-receptor, known as R5 viruses. The implication is that it is more important for a vaccine to protect against these R5 viruses than against X4 ones. It may be that the intact human immune system is well able to control X4 viruses anyway, so they only become a problem late in HIV disease when the immune system is seriously damaged.

Some newer forms of SHIV, and some virulent strains of SIV, do in fact use the CCR5 receptor – but evidence of vaccine-based protection against these viruses is more limited than for X4 forms.

Other problems with animal models
The following problems have also affected animal vaccine research:

  • Some early studies using monkeys were invalid because both vaccines and challenge viruses were produced in human cell cultures. The monkeys became immune to human proteins, which then protected them against viruses grown in human cells but not against the same viruses grown in monkey cell cultures.

  • As viral load measurements only became available in the 1990s, early studies could only look for all-or-nothing protection against infection.

  • In order to get clear-cut results in small numbers of animals, studies tended to use doses of virus far greater than those to which people would normally be exposed.

  • Most studies have used intravenous injection to challenge animals, whereas most human transmission is sexual, across mucosal surfaces. Different mechanisms of immunity may apply to these two routes of infection.

  • Most studies have challenged the animals when the initial response to the vaccine is at its peak, a few weeks after the last vaccination, rather than waiting and relying on 'immune memory'. The effectiveness of a delayed response would be essential for useful long-term protection of vaccinated people.


So, when trying to make sense of animal research in HIV, there are several questions to ask:
  • Can we be sure that any 'protective' immune response was actually directed at the virus?

  • How similar was the route of exposure, the quantity of virus, and its potential to cause illness, to the situation with infection of humans by HIV?


To address some of these issues, the United States National Institutes of Health has established a project to test a number of the leading vaccine ideas in the same way in the same species of monkey (rhesus macaques) against the same challenge viruses. However, even this is unlikely to cover more than a small selection of potential vaccine strategies.

Eventually, when some of these vaccines have been tested for efficacy in humans, animal research may increase in value. For the time being, it can only give clues as to what might work and cannot provide definite answers.