Types of HIV vaccines

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. Despite some encouraging evidence of immune responses in people, it is unclear whether many of these would prevent HIV infection.

Typically, vaccines are administered to large numbers of people at high risk of infection. After a certain time, the vaccinated participants’ experiences are compared to those of people who received a placebo. As described in What an HIV vaccine would have to do, this may involve assessing the antibodies present in their blood, or the response of their CD8 T-cells to HIV in the test tube, or looking for HIV seroconversions in the trial participants.

Researchers have explored a number of strategies that they hope will produce protective immune responses. These include:

  • Live attenuated vaccines.
  • Inactivated vaccines.
  • Recombinant sub-unit vaccines.
  • Modified envelope vaccines.
  • Peptide vaccines.
  • DNA vaccines.
  • Recombinant vectored vaccines.
  • Other vectors.
  • Replicons.
  • Vaccines against viral toxins.

More often than not, studies use a combination of the above types of vaccine in ‘prime and boost’ vaccines, in which two or more different vaccines are used to try and broaden or intensify immune responses. Examples include a vector virus to prime a T-cell response with a subunit (peptide) booster or DNA vaccine to produce antibodies, or two different vector viruses expressing the same gene sequence.

Live attenuated vaccines

One of the most powerful ways to create vaccines is by weakening or ‘attenuating’ the pathogen. These defective viruses are harmless to people, but stimulate the body to produce an immune response. Creating live attenuated vaccines normally involves deleting genes that protect the virus against the immune system, but which are not essential for its reproduction. The measles vaccine is an example.

Live attenuated HIV vaccines are currently considered unsafe, after research in monkeys indicated that a live-attenuated vaccine, made by deleting the nef gene, protected monkeys against SIV, but caused AIDS, albeit more slowly than the normal virus.1,2

However animal research into live-attenuated vaccines continues for several reasons. This is because vaccines used in the above and similar experiments have demonstrated considerable efficacy, and it is important to determine the type, magnitude, breadth and anatomical location of the immune responses elicited by live-attenuated vaccines both to establish better correlates of immunity and in the hope that such responses can be produced by other means.

Inactivated vaccines

Creating vaccines based on inactivated or ‘killed’ viruses is another classic technique, which was used in creating the first successful polio vaccine. However, the technique is considered risky, as vaccine recipients could easily be infected with HIV if the inactivation process should fail. There have been no claims of a significant level of success with these types of vaccine for HIV, although some, such as Remune, an HIV preparation with envelope protein gp120 removed, were investigated as possible therapeutic vaccines for people already infected with HIV.

Recombinant sub-unit vaccines

Recombinant sub-unit vaccines stimulate antibodies to HIV by mimicking proteins on the surface of HIV. A range of HIV proteins has been produced as potential vaccines for HIV. Initially, the main targets for vaccine developers were the viral envelope protein gp120, and its precursor gp160, in the hope that they would prevent HIV entering human cells. These were the basis for the AIDSVAX vaccines. More recently, vaccine developers have experimented with other HIV proteins, including regulatory proteins such as tat.

Modified envelopes

Other strategies for stimulating the immune system to produce antibodies have stemmed from better understanding of the way HIV’s proteins interact with the cells they infect. For example, HIV’s proteins are often hidden from the immune system by a coating of sugar molecules: removing some of these molecules from the protein’s surface may lead to neutralising antibodies that can act against the virus. Secondly, there are ‘variable loop’ regions within the virus’s proteins. In these regions, mutations and changes in the protein’s structure have no effect on the virus’s ability to replicate and cause disease, but they enable it to escape from immune responses directed against those regions by acting as ‘decoys’. Studies have shown that removing parts of these loops produces stronger antibody responses. For more, see Humoral immunity: broadly neutralising antibodies in the section What an HIV vaccine would have to do.

Peptide vaccines

Instead of vaccinating with a whole protein, another approach is to use a fragment of a protein, called a peptide, which consists of a few amino acids. A vaccine containing the V3 sequences from several strains of HIV has been used in animals and produced antibodies able to neutralise several laboratory-adapted virus strains. Peptide vaccines have been tested in HIV-positive patients, with some antibody and cellular immune responses against HIV.3,4 Linking a peptide to a lipid has also been explored as an HIV vaccine technique. The lipid carries the peptide directly into cell membranes where it can be presented to the immune system with maximum efficiency. A number of preliminary clinical trials of such vaccines have been carried out and a Phase II trial using lipopeptides as boosters for canarypox vaccines is now underway at six sites in France. The ANRS VAC 18 used LIPO-5, which contains five lipopeptides from the gag, nef and pol genes corresponding to more than 50 epitopes.

DNA vaccines

DNA vaccines are small pieces of DNA containing genes from HIV, which can be grown in bacteria. After injection, the host’s cells effectively make the vaccine themselves by expressing the HIV genes. Although they work well in mice, it has been more difficult to get DNA vaccines to work in primates, including humans, as it is difficult to get enough DNA into each injection. There are also safety considerations inherent in the design of DNA vaccines, since the genetic material of HIV could effectively result in infection with the virus.

A further problem is that a single mutation in HIV’s genetic material can be sufficient to undermine the protection of an HIV vaccine. In one study, in which eight monkeys were vaccinated and challenged with the virus, one monkey became sick and died within six months of initial infection after its virus mutated to be resistant to the vaccine.5 Although a range of DNA vaccines could be used, this would result in even larger doses of DNA being needed. DNA vaccines that trigger the production of cytokines have also been tested. Experiments in monkeys show that this approach works surprisingly well, but this was less successful in human studies.6

Recombinant vectored vaccines

Recombinant vectored vaccines are most often used for vaccines that attempt to stimulate cellular immunity, as the vaccine acts more literally like an infection than vaccines which simply contain proteins or DNA. They are made by incorporating fragments of HIV into the shells of viruses that can infect cells but cause no or few symptoms, such as the canarypox viruses or adenoviruses. These vaccines infect cells and deliver their package of HIV components into the cell, causing it to display immunogenic epitopes. Most vector vaccines set up an ongoing but harmless infection within the body and therefore set up a lasting immune response to HIV. Vector vaccines have been shown to produce stronger HIV-specific cytotoxic T-cell (CD8) responses in animals and humans. Researchers are working on the bird viruses fowlpox and canarypox, and bird-adapted strains of the smallpox virus vaccinia, such as NYVAC and modified vaccinia Ankara (MVA).

The vaccine used in the STEP trial was an adenovirus vector, and one component of the vaccine used in the RV144 trial was ALVAC, a canarypox vector vaccine. One complication of vector vaccines is that the immune response to the HIV components and the immune response to the viral shell – which may already pre-exist within the body if it has ‘seen’ the complete virus before – may interfere with each other. This is what appeared to happen with some vaccine recipients in the STEP study.

Other vectors

Other viral vectors currently being studied with HIV or SIV in animals include rabies, measles, poliovirus, herpes simplex, human rhinovirus, influenza and pertussis.

Measles is of particular interest because the live attenuated measles vaccine in common use is extremely effective in generating long-lasting immune responses when given to infants. This might be ideal to protect young people in countries where HIV is widespread.

The recombinant rabies virus vaccine potentially has a number of advantages. Since few people are vaccinated against rabies, the attenuated rabies virus infects most human cells but does no damage and it may produce ongoing exposure to HIV antigens in the body. Research in mice has found that a rabies-based HIV vaccine produced HIV-specific neutralising antibodies and cytotoxic T-cells that targeted HIV-infected cells.7

One recent vaccine that has caused considerable excitement from its results in animal experiments used cytomegalovirus (CMV) as its vector.8 CMV is carried by 50% of US adults and 90% of people in sub-Saharan Africa, so what was set up was a ‘superinfection’ with a new strain of CMV rather than a new infection. Half the animals given the vaccine developed undetectable viral loads when subsequently infected with SIV and over the course of two years, the persistent immune response set up by the vaccine appeared to be eliminating SIV-infected cells. CMV, however, causes AIDS-defining illnesses in the immune-suppressed, and there are concerns about the safety and applicability of this approach in humans.

Replicons

Replicons have the same physical properties as viruses and viral vectors, including the ability to enter cells of specific kinds, but they have the advantage of not reproducing after entering the human cell, so there is little or no immune response to the carrier virus. Thus, one replicon system could be used repeatedly in the same person, to deliver a series of different vaccines or gene therapies.

The three leading replicon systems for HIV vaccines are based on Venezuelan equine encephalitis (VEE), Semliki forest virus (SFV), and adeno-associated virus (AAV). All three have shown some success in animal studies. Papillomaviruses have also been developed as the basis for replicons, which appear to offer the possibility of mucosal immunity to HIV antigens following oral immunisation in mice.9

Vaccines against viral toxins

Vaccines can be made against toxins that bacteria and viruses produce as well as against parts of the mature virus. An example is the tetanus toxoid vaccine. It is an inactivated version of the bacterial toxin the tetanus bacterium produces, and it induces antibodies against the toxin itself.

HIV produces several harmful proteins that could be vaccine targets. The most promising so far is the tat (transactivator) protein, which is produced early on in the viral lifecycle, before HIV integrates into the host genome. It stimulates the host cell’s genes to become active and, released outside the cell, influences immune cells to develop in directions that make them more receptive to HIV.

The tat protein is so important to HIV that it is highly conserved, and studies have shown that HIV in people with high levels of anti-tat antibodies progresses more slowly to AIDS, so a tat vaccine might also act as a therapeutic vaccine too. A small trial involving 47 volunteers in Italy ending in 2006 produced a strong immune response in 80% of subjects given it.10 A later trial involving 87 volunteers was given an “ad hoc exploratory interim analysis” by the team in 2010; they claimed that their results showed that immunisation with tat was safe, induced durable immune responses, modified the pattern of CD4 and CD8 cellular activation and increased the CD4:CD8 ratio.11

This was not an uncontroversial finding. Commentators said that, as an open-label study without a placebo group, it was difficult to comment on the comparative immunogenicity of the tat vaccine, and that the ad hoc exploratory interim analysis was a discredited way of analysing data as it could selectively highlight findings that appear to show an effect when there is no real effect. Lead researcher in the development programme, Barbara Ensoli of Istituto Superiore di Sanità in Italy, sued another researcher who criticised protocol changes and violations in the 2006 trial. In addition, some scientists are extremely concerned about tat’s possible toxicity; studies have found that it has a multiplicity of other systemic effects. In particular, it was first detected because it caused the angiogenesis (proliferation of blood vessels) seen in Kaposi’s sarcoma, and there are fears it could have generally carcinogenic properties.

Nonetheless the Italian team studying it is currently preparing larger studies in humans and in 2011 announced that a trial would start in South Africa.

References

  1. Daniel MD et al. Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science 258: 1938-1941, 1992
  2. Baba TW et al. Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques. Science 267: 1820-1825, 1995
  3. Pinto LA et al. HIV-specific immunity following immunization with HIV synthetic envelope peptides in asymptomatic HIV-infected patients. AIDS 13: 335-339, 2002
  4. Kran AMB et al. HLA- and dose-dependent immunogenicity of a peptide-based HIV-1 immunotherapy candidate (Vacc 4x). AIDS 18: 1875-1883, 2004
  5. Barouch DH et al. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 415: 335-339, 2002
  6. Boyer JD et al. Vaccination of seronegative volunteers with a human immunodeficiency virus type 1 env/rev DNA vaccine induces antigen-specific proliferation and lymphocyte production of beta-chemokines. J Infect Dis 181: 476-483, 2000
  7. Schnell MJ et al. Recombinant rabies virus as potential live-viral vaccines for HIV-1. Proc Natl Acad Sci U S A 97: 3544-3549, 2000
  8. Hansen SG et al. Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature, early online publication, doi:10.1038/nature10003, May 2011
  9. Zhang H et al. Human immunodeficiency virus type 1 Gag-specific mucosal immunity after oral immunization with papillomavirus pseudoviruses encoding Gag. J Virol 78: 10249-10257, 2004
  10. Ensoli B et al. Candidate HIV-1 tat vaccine development: from basic science to clinical trials. AIDS 20(18):2245-2261, 2006
  11. Ensoli B et al. Therapeutic immunization with HIV-1 tat reduces immune activation and loss of regulatory T-Cells and improves immune function in subjects on HAART. PLoS ONE 5(11): e13540. doi:10.1371/journal.pone.0013540, 2010
This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.
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This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.