In the absence of curative therapy, preventive measures like sex education, promotion of condoms, prevention of parent to child transmission by using antiretroviral therapy (ART), pre- and post-exposure prophylaxis, topical microbicides, use of highly active ART, screening of blood donors and circumcision have been instituted to control the HIV pandemic. However, despite these measures, it has been found that the estimated number of people with HIV has quadrupled since 1990s. This is because the virus spreads predominantly through sexual mode, the prevention of which requires sustained changes in human sexual behavior, which is difficult to achieve. Further, ART which is therapeutic as well as preventive is not universally available worldwide due to high costs and the drugs themselves are highly toxic. This makes it important to develop vaccine for prevention and therapy of HIV-AIDS.
Despite continued efforts for more than three decades, an effective vaccine against HIV has not been developed. Reasons for this include immunological, experimental, and viral factors like lack of an ideal animal model, incomplete understanding of immune correlates of the disease, multiple portals of entry, ability to cause persistent infection, and huge diversity of HIV-1 strains in the infected individual as well as worldwide.
Since, the majority of the infections around the world are caused by HIV-1 group M and HIV-2 is responsible mainly for localised epidemics in West Africa, efforts are underway to develop a vaccine against HIV-1. The different types of HIV-1 vaccine candidates are discussed below.
1. Live attenuated virus vaccines: Animal studies in monkeys using attenuated SIV (obtained by deleting the nef gene with/ without deletion of other genes) or by using the nonpathogenic humanized SIV (SHIV89.6) have been conducted. These studies initially found that vaccine virus established a lifelong persistent infection in adult monkeys and prevented clinical disease. However, Dnef caused a full blown disease in infant monkeys and reverted to full virulence in some animals. Further attempts to improve the safety profile by deleting more genes resulted in a compro mised protective efficacy. Because of concerns like lifelong infection and revert to virulence, these vaccine candidates could not enter human trials.
2. Whole killed virus vaccine: Such vaccines have the advantage of presenting all the antigens to the immune system for processing. With older vaccine production techniques, there was a possibility of residual infectious nucleic acid with killed virus vaccines, however, these have been overcome with better purification processes. Whole killed SIV (Simian immunodeficiency virus) was unable to protect monkeys against SIV infection. Because of the above safety concerns, these vaccines have not been investigated in humans.
3. Subunit vaccines: Unlike killed vaccines, there is no risk of contamination with residual nucleic acids in subunit vaccines.
a. Env subunit vaccines: Recombinant gp160 subunit vaccine derived from laboratory adapted strains (LAI, MN, SF-2, and IIIB strains) as well as from primary isolates (GNE-8 and CM244 strains) produced in different expression systems like insect cell lines, cancer cell lines, yeasts, etc. have undergone human trials. The major problem with subunit vaccines is that they afford protection only against homologous strains, i.e. they have failed to induce broadly neutralizing antibodies in preclinical or clinical studies. Examples include: AIDSVAX B/B (rgp120: MN, GNE-8), AIDSVAX B/E (rgp120: MN, A244) which have undergone phase III trials showed no efficacy.
b. Synthetic peptide: Synthetic peptide vaccines contain epitopes of interest only and completely omit minor or epitopes with deleterious effects. However, they may not be able to elicit immune response against conformational or non contiguous epitopes and are usually less immunogenic than native proteins. These shortcomings are overcome by use of carriers or potent adjuvants. Phase I human trials of synthetic peptides have found that they have low immunogenicity. For example, synthetic peptides from V3 loop of multiple strains linked to a lipid carrier.
4. DNA vaccines: In this approach, codon optimized synthetic genes encoding HIV proteins of interest are engineered into purified DNA plasmids which are injected into the host cells. Proteins expressed subsequently stimulate both the cellular and humoral immunity. Immunogenicity is further improved by co-expression of cytokines, such as IL-12, IL-15, or M-CSF, which serve as vaccine adjuvants, or by adsorbing DNA onto micro-/nanoparticles, and novel delivery methods like electroporation, e.g. PENNVAX®-B (PV), expressing HIV consensus clade B Gag, Pol, and Env with IL-12 or IL-15 plasmid cytokine adjuvants. Phase 1 clinical trials of DNA vaccines have concluded that DNA vaccines are safe and non-reactogenic.
5. Live vectors: HIV viral protein gene sequences like env, gag, pol, and regulatory genes are engineered into live viral or bacterial vectors. Only those vectors which have been rendered replication defective by deletion of essential genes, like New York vaccinia virus strain or those which cannot multiply in humans are used, e.g. canary pox (ALVAC), fowl pox or attenuated modified vaccinia Ankara are used which adds to their safety. Such vectors stimulate cell-mediated immunity and induce CD8+ T cells. A major disadvantage of using live vectors is the immune response against the vector dampens vaccine efficacy. Two phase 2b clinical trials Step study and Phambili study evaluating replication of a vaccine containing 3 defective adenovirus type 5 with one expressing gag gene from CAM-1 HIV strain belonging to clade B, another expressing pol gene from HIV-1 strain IIIB and the last expressing nef gene from HIV-1 strain JR-FL in a 1:1:1 mixture conducted in men who have sex with men and heterosexual individuals were stopped because there was a higher rate of acquisition of HIV among vaccinees.
6. Prime boost strategy: Prime boost strategy uses two different vaccine types wherein priming is done with one vaccine and boosting with another. This strategy has been found to be more effective than repeat doses of the same vaccine in preclinical studies. These findings have been applied to HIV vaccine. Several approaches have been studied. These include DNA prime + subunit protein or vector boost, viral vector prime + protein or heterologous viral vector boost, and vector prime + vector boost. Examples include RV144 trial (consisting of recombinant canarypox vector vCP1521 prime and AIDSVAX B/E rgp120 boost) which has undergone phase 3 trials and HVTN 505 (priming dose using DNA gag, pol, and nef from HIV-1 subtype B and env from subtypes A, B, and C, and booster using live vector rAd5 subtype B containing gag-pol and env from subtypes A, B, and C) which has completed phase 2 clinical trials. While RV 144 showed moderate efficacy, HVTN 505 trial failed to demonstrate any efficacy.
7. Preventive or therapeutic vaccine: A preventive vaccine would be used before a person is exposed to HIV and may eliminate the virus at the point of entry, or reduce the initial peak viremia, lower the viral set point and eliminate virus, and/or stop the progression to AIDS. The vaccine candidates described above are all preventive vaccines. A therapeutic vaccine will be used in a person who is already infected by HIV and will augment immune responses against HIV helping it to control HIV replication and stop the progression to AIDS. Several strategies like killed virus, subunit, viral vectors, etc. have been tried but they have shown limited efficacy. The different types of vaccine preparations against HIV are elaborated in Table 1.
Table1. Candidate HIV-1 vaccines that have entered efficacy trials
Table1. Candidate HIV-1 vaccines that have entered efficacy trials (Contd.)
Of the several HIV vaccine candidates, only six HIV-1 candidates have reached efficiency trials to date. A list explaining the salient features of these trials is given in Table 21.7. Among the 6, only one vaccine trial ALVAC HIV (vCP1521) + AIDSVAX B/E (RV144) which was started in 2003 and published the results in 2009 has shown moderate efficacy. The trial employed a prime boost strategy which was proven to be effective from previous trials and involved priming with ALVAC-HIV (canarypox vector expressing gp120 from clade E , gag, and protease from clade B, from Sanofi Pasteur) followed by a boost using the AIDSVAX B/E (containing rgp120 from MN strains from Vaxgen).
It was based on the concept that the prime boost strategy would induce CD4+ and CD8+ cells as well as binding and neutralizing antibodies which would then recognize and destroy any HIV strains before the infection becomes established. Priming using ALVAC HIV was done using 4 doses at 0, 4, 12 and 24 weeks followed by boosting with 2 doses of AIDSVAX B/E at weeks 12 and 24 respectively. It was the biggest HIV vaccine trial conducted involving 16402 participants from Thailand and studied the efficacy of the vaccine in preventing infection from sexual exposure. Apart from being the largest study, it had a robust study design (randomized control trial, double blinded and multicentric). It reported an efficacy of 31%.
A study was done by the same group later to identify the immune correlates of RV144 vaccine trial. It found that IgG antibody binding to scaffolded V1V2 Env antigen correlated inversely with acquisition of infection, and IgA antibody binding to Env antigen correlated directly with acquisition of infection.
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