|Year : 2003 | Volume
| Issue : 4 | Page : 225-232
HIV-1 therapeutic vaccine: A ray of hope
DR Arora , V Gautam , B Arora
Department of Microbiology, Government Medical College, Chandigarh - 160 022, India
Department of Microbiology, Government Medical College, Chandigarh - 160 022, India
The human immunodeficiency virus (HIV) epidemic is still in its early stages, and a marked increase in global prevalence is projected for the next coming years. Neither behavioural therapies nor current antiretroviral drugs are likely to have an impact on this silent epidemic. Current antiretroviral drugs are too expensive for the developing countries, and there are major problems of adherence, resistance and toxicity, which limit their application and efficacy. The main problem facing us, as inhabitants of a single world, is to prevent further infections regardless of where they occur, and this requires a vaccine programme. A successful immunotherapeutic HIV vaccine has the potential to overcome these problems, and would be a valuable advance. To accelerate the development of an HIV vaccine, additional candidate vaccines must be evaluated in parallel in both industrialized and developing countries. This will require international collaboration and coordination and critical ethical issues will need to be addressed. The probable triple cocktail of the future for global HIV prevention will be vaccination, anti-retroviral therapy, and not the least, behavioural therapy.
|How to cite this article:|
Arora D R, Gautam V, Arora B. HIV-1 therapeutic vaccine: A ray of hope. Indian J Med Microbiol 2003;21:225-32
Since the beginning of the epidemic, estimates suggest that more than 60 million people have become infected and more than 20 million people have died of HIV/AIDS; including 3 million deaths in 2001 alone, figure that dwarfs the numbers killed by terrorist attacks. An estimated 40 million people worldwide are living with HIV/AIDS and an estimated 14,000 people become infected each day. A recent analysis describes that another 45 million people will likely become infected with HIV by 2010.
Of the global total of people who are living with HIV, 95% live in developing countries. India, where 3.97 million Indians are living with HIV/AIDS, has the highest number of HIV-infected persons in Asia. Despite aggressive educational campaigns, it is estimated that 4% of the US population continue to engage in activities that have a high risk of HIV transmission. Highly active antiretroviral therapy (HAART) is often associated with acute and chronic toxicities, the development of resistant virus can limit its effectiveness, and the drugs are too expensive and difficult to administer in most third world settings.
As the number of people infected with HIV continues to expand, the annual number of deaths worldwide can be expected to increase. Because of the limited success of behavioural strategies and therapies designed to prevent the spread of HIV, the development of an HIV vaccine may represent the only way to slow this pandemic. The scientific challenges presently are:
i. Genetic variability of HIV
ii. Rapid and resistant replication of virus
iii. Spread of HIV by way of cell-associated virus
iv. Immunological correlates of HIV protection not known
v. Long latent period between initial infection and the development of symptoms
vi. Latency in some cells
vii. Lack of an appropriate animal model for AIDS
viii. Live attenuated viral vaccines might recombine with wild-type viruses and revert to a virulent form
ix. Persistent immunity may require persistent expression of a vaccine
Genetic analyses of HIV strains isolated from different parts of the world has revealed that several HIV genes exhibit extensive sequence heterogeneity, particularly in the gene coding for the viral envelope proteins, gp120 and gp41. So far, nine genetic subtypes (A-K) within group M (main) as well as groups O (outlier) and N (new or non-M, non-O), have been characterized. Such subtypes have envelope gene sequences that vary by 20% or more between subtypes. The prevalence of intersubtype recombinant strains is increasing and creates even more HIV-1 antigenic diversity. These are referred to as circulating recombinant forms (CRFs) and the viruses originally identified as subtype E and I are now considered as CRFs.,
To contend with the genetic diversity, there are currently two general approaches in selecting vaccine strains. The first is based on using isolates of a particular subtype, sometimes from a geographic region where the vaccine is intended for use. The second approach is to construct either a consensus sequence or an ancestral sequence reconstructed on the basis of an evolutionary model. This minimizes the genetic differences between vaccine strains and contemporary isolates, effectively reducing the extent of diversity by half. 
Monkeys are the favoured animal model for testing vaccine strategies (researchers no longer use chimpanzees for ethical and cost reasons). Although HIV does not infect monkeys, a cousin simian virus, simian immunodeficiency virus (SIV), does. Although some researchers question whether the monkey model truly mimics HIV in humans, the field at large has embraced it as the best way to determine which vaccine strategies hold the most promise. But a slew of recent monkey experiments has raised questions about most of the vaccine approaches now being pursued.
A major stumbling block for the rational development of HIV vaccines has been the lack of information on the immunological correlates of protection against HIV/AIDS.
| ~ Correlates of Protective Immunity|| |
Ongoing HIV vaccine development strategies are targeted at the two major types of immune responses, humoral and cell-mediated immunity, and include strategies to induce both of them. Although a wide variety of antibodies is induced in HIV-infected patients, only a few of them neutralize heterologous strains or primary field isolates. The generation of HIV vaccines that are capable of inducing strong cross-clade neutralizing mucosal and serum antibodies is complicated by the high variability of the HIV Env proteins. Unfortunately, the lack of correlation between genetic subtypes and neutralisation makes vaccine development more complex.,
Although cytotoxic T cells (CTLs) are detected early in the course of the infection, they are unable to control viral replication completely and prevent the subsequent development of immunosuppression. Recently, several hypotheses have been put forward to explain this failure. First, the biological characteristics of the virus itself which, by integrating into quiescent CD4+T cells, cannot be detected by the immune response and allows him to behave like a Trojan horse. Second, the rapid alteration of the immune system in the absence of therapy might also explain the lack of eradication of the virus. Lastly, viral escape, perforin imbalance in cytolytic granules, dysmaturation of CTLs and downregulation of the HLA class 1 molecule by the Nef protein may all be additional contributing factors., It has also been postulated that HIV specific CD4 helper T cells are the main target of the HIV and are preferentially destroyed very early in the infection in the absence of antiviral therapy., This may lead to permanent lack of CD4+T cell helper function.
Antibody titres can be sustained at high levels in serum and in much lower concentrations in mucosal secretions. For HIV, the most vulnerable steps may be its crossing the mucosal membranes and its journey to the local draining lymph node. IgA antibodies are induced in the genital tract in natural infection and have been shown in vitro to prevent the transcytosis of HIV virions through an epithelial cell layer. Data collected from HIV exposed but uninfected individuals suggest that mucosal immunity may block sexual transmission.,
Recently, the innate immune response representing the first line of defence against pathogens started to merit further attention in its role in combating HIV infection and disease progression. Interferon producing cells, which are precursors of dendritic cells that enhance Th2-type responses, can contribute in a notable way to suppress HIV replication by engaging both innate (e.g. NK cells) as well as adaptive (e.g. CD8+ cytotoxic cell) antiviral activities. Another cell type involved in innate immune responses is the CD8+ cell showing noncytotoxic antiviral responses (CNAR).
| ~ Ideal HIV Vaccine|| |
It is currently impossible to state with certainty all the qualities of an ideal therapeutic vaccine candidate. Ideally, an HIV vaccine would induce complete protection from infection, also known as sterilizing immunity. However, we can speculate on what constellation of features we would like in a candidate before we take it forward to (large-scale) clinical trials [Figure:1].,
| ~ Candidate Vaccines Under Trial and Partial Success Stories|| |
Before the HAART became available, a number of strategies were pursued to assess the utility of vaccines as therapies for HIV-1 infected individuals (therapeutic vaccines).
The first-generation HIV candidate vaccines were based on the envelope proteins of HIV, especially gp120. Second generation candidate vaccines are designed using either live vectors or naked DNA that codes for different HIV genes. Third-generation vaccines, based on regulatory nonstructural proteins of HIV, such as Tat, Rev, Nef have also emerged. Some immunization protocols use a combination of two different vaccines to induce broader and/or stronger anti-HIV immune responses.,,
Remune is a whole killed HIV-1 with a clade A envelope and clade G gag, and it is depleted of gp120 [Table - 1], [Table - 2].
It has been developed over the past 10 years, and is one of the first candidate HIV immunotherapeutic vaccines to have entered large scale phase III clinical trials. It seems unlikely that Remune by itself will prove to be of significant therapeutic benefit. Nonetheless, valuable insights into the protective mechanisms and approaches to therapeutic vaccine development have been gained. Also, by virtue of the duration and scale of investigation of the vaccine, Remune might prove to be a useful benchmark for future candidates. Further phase III studies have just begun in Europe and the USA, and are designed to examine in a rigorously controlled manner the impact of Remune in patients on HAART.,
The use of envelope proteins as constituents of potential HIV immunotherapeutic vaccines has shown little promise as judged in different studies. Although the first generation of HIV envelope vaccine candidates has been shown to be immunogenic and safe to use in phase II human trials, their failure to induce antibodies that could neutralize primary isolates delayed phase III efficacy trials.,
Clinical trials using multivalent chimeric peptides derived from diverse HIV proteins, as well as several studies in primates, confirmed that a peptide-based approach might not be suitable for inducing broadly cross-neutralizing antibodies. Nevertheless, further improvements of peptide vaccines could provide an efficient tool for inducing selective cellular immunity against multiple targets.
Recombinant technology has been used to engineer second-generation vaccine candidates. Recombinant canarypox virus vectors do not infect human cells and they have a good safety record in humans so far. Experimental work has suggested that if a reliable means of targeting the canarypox vaccines to dendritic cells can be found, then this will enhance the strength and duration of antigen specific CTL responses.
Studies in mice as well as primates have demonstrated that DNA vaccination can induce antigen-specific immune responses against HIV-1. Yet another type of approach has been to use a DNA vaccine cassette, which expresses multiple HIV accessory genes. The potentially important finding when mice were immunized with such similar constructs was that there was a very broad recognition and induction of cell-mediated immune responses to a divergent range of clade B viruses. This broad response would be a requirement of any successful prophylactic or therapeutic vaccine.
| ~ Future Strategies|| |
When the search for an AIDS vaccine began, the focus was on preparations that contained genetically engineered versions of HIV surface protein which would trigger an antibody response capable of “neutralizing” the virus before it can establish an infection. The AIDS vaccine that has moved ahead on this concept in human trials is a genetically engineered version of HIV surface protein made by VaxGen, US. However, monkey studies with AIDS vaccines have completely failed to elicit antibodies that can neutralize the virus. As a result, many have shifted their attention to the arm of the immune system that dispatches killer cells, tiny missiles that seek infected cells and obliterate them. Because killer cells, by definition, can do their thing only if an infection has already occurred, the goal now is not prevention of infection but of disease. Some monkey experiments have given heart to those taking this approach but other monkey studies have raised doubts.,,
The next vaccine in line, made by Aventis Pasteur, “primes” the immune system with a live-virus vector, canarypox, that carries HIV genes, and then “boosts” it with gp120. Although the prime-boost concept still holds center stage, presently naked DNA is the priming vector of choice, followed by a boost with a viral vector. With time, we expect more exotic vectors, such as Venezuelan equine encephalitis [AlphaVex, International AIDS Vaccine Initiative (IAVI); South Africa, US], and unusual carrying systems, such as Salmonella More Details shutting in a DNA vaccine (Institute of Human Virology, IAVI, US) which are under preclinical trials.,,,
It would clearly be an advantage if we could improve on the immunity elicited by an antigen by combining it with a more effective adjuvant. A useful summary of the important adjuvants is included in a review of HIV vaccines by Nabel et al.
Alloimunisation / Allogeneic vaccine offers a potential approach for both therapeutic and prophylactic HIV vaccines. Although alloimmunisation is still only a theoretical tool in HIV vaccine design, the evidences suggest that the use of this approach clearly requires further exploration.,
Heat shock proteins (HSPs) are shown to have mucosal and systemic adjuvent activity by stimulating antigen presenting T cells to generate the three CC-chemokines (CCL 3,4,5) and interleukin-12., Both of these latter alternative strategies of immunization are independent of HIV mutation and CTL escape. The mechanism of protection does not focus on either CTL or neutralizing antibodies, but on integrating the immune repertoire of innate and adaptive immunity.,,
| ~ Quest Study (GW PROB 3005)|| |
This project is an ongoing international trial initiated in 1998 which has enrolled the largest prospective cohort of patients with primary HIV infection to date. Patients are treated at the time of seroconversion with quadruple antiviral therapy for at least 72 weeks. This is followed by a randomized double-blind placebo-controlled three arm phase: HAART, HAART plus ALVAC HIV vCP 1452 plus Remune. Its aim is to test the possibility of long-term virological suppression six months after discontinuation of all treatment. Results are expected in the year 2003.,
| ~ Vaccine Trials in India|| |
After losing an 11-year battle to control AIDS with slogans, condoms and a $100 million World Bank loan the Indian government in 1998 has launched a programme to develop a vaccine against the disease despite skepticism in the West that this is still a distant dream. Under the Indo-US program started in 1987, Indian teams working on the project include the government Department of Biotechnology (DBT) and four other institutions: All India Institute of Medical Sciences (New Delhi), National Institute of Communicable Diseases (New Delhi), Christian Medical College (Vellore), and National AIDS Research Institute (Pune). Under the terms of a new partnership with National Institute for Cholera and Enteric Diseases (Kolkata, India) in March 2001, the International AIDS Vaccine Initiative (IAVI) will fund a US biotechnology company (Therion Biologic) to develop a vaccine for HIV subtype C, based on the Modified Vaccinia Ankara (MVA) pox virus vector.
| ~ Summary and Conclusions|| |
The first phase I trial of an HIV candidate vaccine was conducted in the US in 1987, using a gp160 candidate vaccine. To date, more than 30 HIV candidate vaccines have been tested in 60 phase I or phase II trials, involving more than 10,000 healthy volunteers. However, only two vaccine approaches were further submitted to phase III clinical trials.
Most of the trials have been conducted in the USA and Europe, although some have also been conducted (or are being conducted) in developing countries including Brazil, China, Cuba, Haiti, Kenya, Thailand, Trinidad and Tobago, Uganda and India. Trials in developing countries are important for several reasons. First, most infections occur in such countries, where an effective vaccine would eventually be used and be most beneficial. Second, to produce valid and timely results, phase III efficacy trials need to be conducted in populations with high incidences of HIV infections. Third, the genetic and antigenic variability of HIV may necessitate testing candidate vaccines in different areas of the world. Finally, it may be necessary to evaluate how different routes and/or cofactors for HIV transmission influence vaccine protection. In the near future, trials are envisaged in regions of the world where multiple subtypes are circulating..
The usual time span of over 10 years between a vaccine concept and its Phase III clinical trial is the worst dilemma of HIV vaccine research. In addition to intensive costs and the ethical, political and geographical issues associated with implementations, Phase III clinical trials take at least three years to conduct. In conclusion, it could take at least another 5-10 years until we obtain the first results on the efficacy of the cost promising, recently developed and novel HIV/AIDS candidate vaccines in man.
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