Current Vaccine Strategies Against Hiv

Introduction In the last decade HIV has become a global epidemic, in 2009 there was a record of 33.3 million people living with HIV and 1.8 million deaths by AIDS (WHO, 2009). HIV is a condition in which infection occurs by the lentivirus; these viruses derive from the retroviridae family and are slow acting viruses, hence characterised by their long incubation period. Luc Montagnier and his team were the first to discover the two main strains of the Human immunodeficiency virus in 1983, HIV-1 and HIV-2. The HIV-2 strain weakens the immune system at a slower rate than HIV-1 and is somewhat constricted to the Western African region (Kalichman et al. 2006). After contamination, the disease occurs when crucial cells within the human immune system are infected; these immune cells include T-helper cells (CD4+ T-cells), macrophages and dendritic cells. Although there is a strong humoral and cell mediated response, HIV is a very mutable virus and after a period of incubation HIV-1 leads to infection within the CD4+ T-cells, subsequently this leads to decreased levels of CD4+ T-cells caused by direct viral killing, increased rates of apoptosis and death by CD8 cytotoxic lymphocytes. HIV is also able down regulate MHC 1 molecules, which reduces detection by CTL. Dangerously low levels of CD4+ cause a loss of cell-mediated immunity, and if left untreated it eventually leads to AIDS and in turn this leads to opportunistic infections, which is the main cause of death (Hall et al. 2011). Considering that HIV is such a large epidemic disease, causing a high mortality rate there is no such vaccine developed as of yet, to prevent HIV infection with a significant level of success. Animal models Till date animal models have suggested the possibility of creating a successful vaccine. These include: Live attenuated vaccines It was in the 1930s, the Simian Immunodeficiency Virus (SIV) was thought to have mutated into a human form, HIV-1. Knowing this fact researchers accept SIV will have the similar properties of HIV-1 when working with them. Previous evidence had shown that nef-deleted mutants of SIV could give protection against the pathogenic SIV in rhesus macaques (Hofmann-Lehmann, 2003); this led to the development of a live attenuated HIV vaccine approach. Eleven rhesus macaques were injected SIVsmE543-3; all the macaques had acute phase infection, and it was suggested that cellular responses of replication control was crucial for protection against this strain. Sugimoto et al. (2010) suggested that the limitations of this study included recombination between the vaccine and viruses, an increased gp120 glycosylation and the nef-mutant SIV displayed a life-long low-grade viral infection. Although it slowed progression to AIDS, it did not protect from AIDS nor did it prevent super infection from other types. Further deletions or mutations could have been made to manipulate more of the properties but this would have resulted in a compromise of the protective effect that the live attenuated vaccine had somewhat presented (Blancou et al. 2004). Due to obvious health and safety reasons live attenuated vaccines have not yet been progressed into human trials (Whitney and Ruprecht, 2004). Inactivated vaccines The most obvious reason of developing an inactivated vaccine is destroying the viral envelope antigenicity, unlike the previous strategy. Poon et al. (2005) carried out a study where the viral had successfully been inactivated. The method in which the virus was inactivated was by sub-lethal doses of formalin and then heat inactivation (62Oc). The results of this within mice and macaques showed a reasonable amount of antibodies, which were able to neutralise heterologous primary isolate of HIV. This shows that although antigenicity of the viral maybe low it is still sufficient enough to induce an immune response. The main advantage of this approach is that it is much safer to work with than a live virus and showed that antibody response might play a crucial role in neutralising isolates of HIV. Human trials When the vaccines within animal model trials look promising they are able to be tested within human efficacy trials. Till date there have been three different vaccine strategies trialled. Subunit vaccines - Envelope-based subunit vaccines The earlier trials of HIV-1 enveloped based subunit vaccines within animal models suggested that the recombinant glycoprotein, gp120, brought out neutralising antibodies against homologous vaccine strain also enabling to sterilise immunity (Mascola et al, 1996; Berman, 1990). However, it was thought that the dose and strain have played a major role in this positive outcome. Dimmock (1993) suggested that neutralising antibodies were able to aggregate the virus by binding to specific epitopes on their surface, which in turn prevented entry within the host's cells and destruction through the complement and phagocytosis. Another similar vaccine was based on monomeric gp120 with variations within VaxGen's envelope subunit vaccine (AIDSVAX). This aimed at inducing envelope specific humoral immune responses. Two double-blinded, placebo controlled phase III efficacy trials, with high risk subjects were undertaken to see the effects of this vaccine; one based within USA (Flynn et al. 2005) and the other within Thailand (Pitisuttithum et al. 2006). The trial Flynn and his team carried out consisted of 5403 participants, mostly of who were homosexual men. These participants were immunised with two subtype B (gp120s). The trial Putusyttithum (2006) and his team carried out consisted of 2527 participants, mostly of whom were drug users, they were given a subtype E (CRF AE) and subtype B (gp120s). The participants were given 7 IM doses of 300 µg of antigen and alum (aluminum hydroxide). Although these continuous booster shots were given and strong antibody responses were seen at binding and neutralising, both of these trials did not give HIV protection to the participants, with 0% efficacy. This suggested that the neutralising antibodies response alone was not sufficient enough for protection against HIV-1 infection. There are many challenges within this strategy such as inducing NAb that are broad enough to attack mutating epitopes or inducing NAb against functional gp120 and gp41 proteins which are masked by glycosylation and trimerisation or the proteins redirect the antibody responses away. (Cohen, 2006). Adenovirus vector Cell mediated immunity was the evident choice of strategy after the failure of the previous two trials, due to observations such as: The relationship between the detection of HIV- specific CD8+ T-cells and the reduction of the primary viremia suggests that CD8+ T-cells play a role in the control of virus replication (Owen et al. 2010). Several HLA class I alleles (HLA-B57, HLA B-27, HLA-B63) are associated with the slow disease progression (Thomas et al. 2009). Early selection of CTL escape during primary infection and the rapid increase of viral loads in macaques infected with SIV after experimental depletion of CD8+ T-cells (Jin, 1999). A trial carried out with participants within USA, Australia and the Caribbean in 2005 (modified), used adenovirus vector, this was called the STEP trial. It consisted of mostly homosexual men and was a double blind, placebo controlled trial, with 3000 participants. HIV-1, clade B was injected into the deleted E1 region of the adenovirus, which was a mixture of three recombinant replications of the defective subtype 5 vector (proportion of 1:1:1). The vaccine was given followed by a booster on week 4 and 26 (1 ml, equivalent of 3 x 1010). Observations showed that an increased rate of HIV-1 acquisition was seen in those who were vaccinated and this was thought to be due to the anamnestic response of Ad5 (Buchbinder et al. 2009). Although a strong T lymphocyte mediated immune response was seen, the trial was halted after the first interim analysis because of the lack of efficacy (0%) of HIV-1 protection. It was also thought that it was prior exposure of adenovirus that resulted in high antibody presence. It was suggested that protection was not seen although high CTL response could be due to reasons such as the CTL response focusing on small amounts of epitopes (narrow breadth) for a long period where HIV-1 epitopes can quickly mutate and escape from this response, therefore strategy. A study with macaques was done which showed that pulsing autologous cells with overlapping peptides were able to increase the extent of vaccine induced immunity. Another challenge is that the virus is able to produce latent reservoirs, and although there may be a sufficient breadth of CTL response it may not be quick enough to act against the latent HIV-1 infection. This can be overcome by introducing vectors such as CMV, which can maintain the level of CTL for controlling the virus (Sekaly, 2008). Canarypox vector and gp120 (subtype B and E) The strong responses of the Vaxgen trial (Thailand) in inducing strong antibody responses led the RV144 trial, with B/E subtype for both humoral and cell mediated immunity against HIV-1. The subtype E was linked to the transmembrane of the gp41 part of the subtype B (LAI, carrying a deletion of the immunodominant region). This trial was the largest till-date, which recruited 16395 participants (in Thailand) and the AIDSVAX was used with a recombinant canarypox vector vaccine (ALVAC-HIV). Again this trial was randomised, double blinded and placebo controlled. However, within this trial the participants were in a community based setting so the risk of HIV-1 infection was not considered. Priming injections were given (50% of tissue culture infectious dose) initially followed by subsequent injections in week 4, 12 and 24. Then the AIDSVAX B/E vaccine was given in week 12 and 24 (300 µg). The trial exhibited a 31.2% risk reduction rate of HIV-1 infection (in vaccinated participants compared to placebo group).It was seen that the highest antibody titres were in the first year (during early infection) and as this dropped so did the efficacy of the protection (Rerks-Ngarm et al. 2009). This trial was crucial in exhibiting how both arms (adaptive and innate) can elicit a sufficient response, for protection against HIV-1 infection, by binding to Fc portions of ADCC-mediating antibodies, IgG1 and IgG3 (through Fc-gamma receptors, usually CD16), which coat the target's surface cell, to release inflammatory cytokines (i.e. interferon-gamma) and initiate destruction of by cytotoxic granules (Cavacini et al. 2003). Conclusion From critically looking at the vaccine strategies developed up until today, the limitations and inefficiency can be seen such as lack of breadth and epitope specific responses exposure to masked functional regions, which need to be addressed before any of these vaccines can be clinically utilised. However, RV144 trial has shown some hope in an effective vaccine development, with a reasonable efficacy rate. the Although saying this, it is still not understood how much quantity of the immune response is needed to fully protect against HIV infection, therefore the progression. Currently, there are 38 new trials in the pipeline, with some in the recruitment stage and some in data analysis stage (HIV Research, 2011).