|Year : 2014 | Volume
| Issue : 1 | Page : 3-7
Human immunodeficiency virus infection/acquired immunodeficiency syndrome Vaccine: Biggest challenge in medical sciences - Some see a hopeless end, while others see an endless hope
Ravishekar N. Hiremath1, Aniket Kulkarni2, S. Bhalla3, Sandhya Ghodke1, S. Sinha4, Renuka Kunte5
1 Deputy Assistant, Director Health, Ranchi Division, Jharkhand, India
2 AFMC, Pune, Maharashtra, India
3 AFMC, Jaipur, Rajasthan, India
4 AFMC, Mathura, Uttar Pradesh, India
5 Advisor (PSM), Delhi, India
|Date of Web Publication||11-Jun-2014|
Ravishekar N. Hiremath
Source of Support: None, Conflict of Interest: None
One of the biggest challenges in the history of mankind has been the development of a vaccine against the human immunodeficiency virus (HIV). This is even more so complicated by the fact that the genetic makeup of the virus undergoes tremendous variations. The advent of a very effective and safe vaccine is a far dream as of now when the vaccine development processes are traditional and in the research process. The need for the hour is the development of an effective vaccine against HIV. The challenges to it are manifold. Starting from the level where the basic pathogenesis of HIV infection poses a great riddle to the development of the effective vaccine, to the arena of a variety of socioeconomic challenges, political pressures and ethical considerations. The research into vaccine development has to be highly coordinated in the midst of all these considerations. This issue is an urgent mission, which demands that governments, policymakers and civil society have to work in unison with the scientists to tackle this huge challenge.
Keywords: Human immunodeficiency virus, immunity, live recombinant vectors, vaccines
|How to cite this article:|
Hiremath RN, Kulkarni A, Bhalla S, Ghodke S, Sinha S, Kunte R. Human immunodeficiency virus infection/acquired immunodeficiency syndrome Vaccine: Biggest challenge in medical sciences - Some see a hopeless end, while others see an endless hope. Indian J Allergy Asthma Immunol 2014;28:3-7
|How to cite this URL:|
Hiremath RN, Kulkarni A, Bhalla S, Ghodke S, Sinha S, Kunte R. Human immunodeficiency virus infection/acquired immunodeficiency syndrome Vaccine: Biggest challenge in medical sciences - Some see a hopeless end, while others see an endless hope. Indian J Allergy Asthma Immunol [serial online] 2014 [cited 2019 Sep 15];28:3-7. Available from: http://www.ijaai.in/text.asp?2014/28/1/3/134202
| Introduction|| |
According to World Health Organization, 34 million people are living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Out of which 2.5 million new infections occurred in 2011 and about 1.7 million AIDS deaths occurred in 2011. Between 1981 and 2007, more than 25 million people world-wide died of AIDS related causes. Though no cure has been found, patients can control the virus and enjoy healthy and productive lives with effective antiretroviral drugs. However only 6.6 million people living with HIV are receiving antiretroviral therapy in low-and middle-income countries and million others are still waiting for access to treatment. 
| Review methods|| |
A search of various contributions in the development of an HIV vaccine was carried out using internet databases like Google and Google scholar including various relevant electronic journals.
| Need for hiv vaccine|| |
AIDS is devastating the health care systems and national economies particularly in South East Asia and sub-Saharan Africa. More than 95% of all new infections occur in developing countries. Medical and human costs of AIDS, according to the United Nations, have actually reversed economic and social development in several countries. This makes HIV/AIDS a serious threat to global health and development. 
The strategy against the virus needs to be global and new as all the aspects viz. prevention, treatment and investigation have to be a part of the comprehensive approach.
To increase access to HIV prevention, a combined plan for both men and woman needs to be in place which will encompass their reproductive health needs. This will not only increase access to condoms but also increase access to voluntary HIV counseling and testing along with treatment and supportive care. This will also address the prevention of mother-to-child transmission.
Developing new prevention tools such as a preventive HIV vaccine could significantly reduce the spread of HIV and AIDS and make universal access to prevention, treatment and care affordable and sustainable. 
| Potential hiv vaccines|| |
The approach in vaccine invent is twofold preventive and therapeutic. Both present a different philosophy of action. The preventive vaccine when administered to the uninfected individuals/high risk individuals will prevent infection and disease. Whereas, the therapeutic vaccines will decrease the viral load in the infected individuals thereby modulating the immune response and hence prevent the development of the disease.  The cost-effectiveness of preventive vaccines is much higher and they do have the potential to eradicate the epidemic.
| Types of vaccines|| |
- Whole-killed/Whole-inactivated vaccines - The active component is an intact virus or bacterium. These lack the ability to spread the infection to humans
- Live-attenuated vaccines - The active ingredient of this vaccine is a pathogen which can multiply inside the host but is unable to cause disease. The vaccine do not cause disease in immune-competent person.
- Subunit vaccines - These are supposed to provide an intense and protective immune response. These are composed of purified pieces of antigens
- DNA vaccine candidates - The active ingredients of these vaccines are the circle of DNA (plasmids) which carry genes encoding the antigens. These antigens are produced inside the human cells when these plasmids are taken up passively. The antigens then train the immune system to work against the targeted pathogen
- Recombinant vector vaccine candidates - Viruses which can actively infect human cells are used to be carry antigens. These vectors are safe to use. Only those viruses are chosen as vectors which are not capable of causing any disease in humans. They are also made devoid of the ability to proliferate in the cells
- Based on recombinant viral vectors, new vaccines expressing a foreign antigen are under intense development. One of the most advanced and most promising vectors is the attenuated, non-replicating poxvirus modified vaccinia virus Ankara (MVA), a safer derivative of the uniquely successful smallpox vaccine. Recombinant MVA is at least sufficiently genetically stable, manufacturable, safe and immunogenic (even in the face of prior anti-vector immunity) to warrant reasonable hope over the feasibility of large-scale deployment 
- Virus-like particles (VLPs) based vaccines for HIV hold great promise in the development of affordable and effective vaccines. Indeed, VLPs are suitable for presentation and efficient delivery to antigen-presenting cells of conformational as well as linear antigens. This can lead to cross-presentation with both MHC class I and II molecules to prime CD4(+) T-helper and CD8(+) cytotoxic T-cells. 
| Hiv vaccine development|| |
None of the effective preventive or therapeutic HIV vaccine is available. Many of the researched vaccines have gone into the clinical trials which takes tremendous time to emerge as safe and effective for use in general population.
The HIV vaccine has to work multifold in the human body. It has to train the body for recognition and destruction of the infected cells and has to activate the immune system to block the infection. The most effective protection from HIV can be achieved by engaging both humoral and cellular mechanisms of the immune response of the body.
There are two major approaches in designing preventive HIV vaccines: Engaging the immune system to block infection and training the body to recognize and destroy cells infected by HIV. International AIDS Vaccine Initiative organization believes that a vaccination strategy that engages both humoral and cellular mechanisms of the immune response will provide the most robust protection from HIV. 
HIV contains a total of nine important genes (env, gag, pol, nef, tat, rev, vpr, vif, vpu). The vaccine can induce immune responses with any of these antigens, but the decision which one to use is the most important one. Based on extensive research studies of HIV specific T-cell responses in infected individuals, commercial vaccine making companies have selected various genes for vaccine production. For example in Ad5 vaccine candidate, Merck selected the gag, pol and nef genes based on extensive studies. ,
The initial days of the vaccine research saw the production of vaccines which contained neutral antibodies against HIV. These antibodies failed to neutralize HIV in infected people. The antibodies could neutralize viruses from the lab culture but not in vivo. Many trials mainly two large efficacy trials confirmed these observations after the AIDSVAX failed. 
T-cells have a pivotal role in controlling HIV infection. Therefore, either the antibody based or T-cell based vaccines are the mainstay of research.  T-cells can slow down the progression of disease in an immunized person who is infected with HIV. It helps in reducing the risk of virus transmission. The T cell response comprises of both its helper (CD4+) and killer (CD8) T cells components.
The highly active antiretroviral therapy (HAART) regimens are very much potential in reducing the HIV viral load. This has opened the gates of hope for therapeutic immunization, based on the idea that viral suppression and the attendant immune reconstitution may provide an opportunity to induce new and more effective T-cell responses targeting HIV.
As the field of vaccine research is furthering on, so have the development of sensitive and specific assays. These assays have readily revealed the properties related with the control of HIV viral load such as IL-2 production and proliferation. It is yet to be determined if the T-cells thus induced provide beneficial responses or not.
One of the properties expected of the therapeutic vaccines is the maintenance of the reduction of viral replication when HAART will be stopped intermittently. This will help in the reduction of viral load even when HAART are not being taken and will also expedite the recovery from the disease.
To support such notion, a French research study showed a statistically significant difference in the post-treatment interruption control of viral load among recipients of a regimen that included HIV lipopeptide vaccine combined with a recombinant canarypox vaccine and IL-2 compared to participants receiving HAART alone. However the limitation of this study was the small number of participants and that the difference in the interruption time before commencing HAART was small. 
One of the recent methods of therapeutic immunization is the use of dendritic cells (DCs). DCs try to process and present the pathogens to T cells. This initiates further immune response. One of the studies which used DCs, claimed an immunologic and virologic benefit in participants with early HIV infection who had not started HAART. 
| Challenges in designing hiv vaccines|| |
Though the most important purpose of vaccine is to help immune system to recognize a pathogenic organism and thereafter help fight against the disease process, the advent of a fully successful HIV vaccine has not been possible. This issue continues to present a great challenge to the researchers despite having understood in a great deal about the HIV and the human immune system.
The path toward the development of an effective and safe vaccine is paved with numerous challenges; some of the pertinent ones are described a below:
- The virus attacks the T-cells itself which are the mainstay of the immune system. T-cells coordinate the overall immune cells' activity against HIV. Therefore, the foremost requirement for the vaccine to function adequately is that the T-cells should itself survive
- The foremost requirement for the researchers has been the identification of the correlates of the immunity for HIV. Till now it has not been possible for scientists to identify the correlates of immunity or protection against HIV. They are still trying to design zvaccines to induce the appropriate immune responses necessary for protection. This is in contrast to the other viral diseases for which successful vaccines have been made. What we are left is still to achieve a human model of recovery from the infection and then the protection from re-infection
- The ever evolving newer strains of the virus is another problem area. The virus is continuously undergoing mutations and recombination's and thus emerging into new strains all the times. This makes the development of a single vaccine that is effective against all the strains impossible. Conventionally, the vaccines have to provide protection against a fixed number of strains
- The human immune system works over two pillars viz. the T-cells and the antibodies secreted by B cells. The researchers have failed miserably to illustrate any antibody response against the HIV infection as of date. Only weak T-cell responses have been elicitated in the laboratory so far with experimental HIV vaccines
- The lacunae in the vaccine research is so dark and glaring that even the question-which part of the HIV antigen will make the immune system recognize the HIV during the actual infection-is still unanswered.
There has been a lack of animal model to prove the effectiveness of an HIV vaccine. This impedes the development of the vaccine in the laboratory. The simian immune virus (SIV) has been used extensively models for research purpose so far. There is an engineered combination of SIV and HIV, which is known as SHIV which may tell us more about the disease progression. Evaluating experimental vaccines in these animals requires an SIV or SHIV analog instead of the actual HIV vaccine candidate used in clinical trials in humans. 
Monkeys (macaque) are used as typical animal model for research in HIV vaccine. SIV or the chimeric SHIV infected Monkeys were used for research purposes. Vaccination induced neutralizing antibodies by well-proven route has however been stalled because of the great difficulty in stimulating antibodies that neutralize heterologous primary HIV isolates.  Virus envelope based some of the vaccines have protected chimpanzees or macaques from homologous virus challenge  but in clinical trials, similar constructs immunized individuals became infected after later exposure to HIV-1.  The main challenges in the use of an animal model are due to differences between HIV and SIV. 
As per findings published in the Journal of Virology, researchers now believe cats may be the key to an HIV vaccine, after peptides in the feline immunodeficiency virus were found to trigger T cells to kill HIV.
| Progress and prospects|| |
Remarkable progress has been made by the researchers, despite the challenges, towards production of vaccine. It was demonstrated in the year 2009 in a clinical trial that HIV infection can be prevented. However the degree of protection conferred was very small. Thereafter, several strong antibodies which were capable of combating numerous HIV variants world-wide have been studied thoroughly.
At the same time, scientists have studied various vectors for HIV vaccine. The vectors can induce a better response against HIV. Some of such vectors are - Ad35 + Ad26; DNA + Ad5; and electorporated DNA/IL12/Ad35. These vectors have moved onto the Phase I trials. Numerous HIV vaccine candidates are in different phases of clinical trials. Vaccine modified vaccinia Ankara B showed effectiveness of 90% during Phase I clinical trial as per researchers in National Biotech Centre, Madrid. 
STEP study (also known as "HVTN 502") was started by HIV Vaccine Trials Network (HVTN) involving 3000-participants in Phase II clinical trial of a novel HIV vaccine called V520 in 2004 and expected to finish in 2009, but ceased much earlier in 2007 as the vaccine was ineffective at preventing HIV-infection.  In the similar way HVTN 505 study was started in 2009 to examine an investigational HIV vaccine regimen with the main goal to test whether the vaccine regimen could reduce the viral load of vaccinated people who later became infected with the virus. Additional information about the vaccine regimen's safety was also expected from the study. However as per review carried out on April 22, 2013 all HVTN 505 study sites immediately ceased administering injections but continued follow-up of study participants as vaccine failed to reduce viral load among 30 volunteers.  Based on the results of these trials, vaccine development strategies were re-examined.
These advances in HIV vaccine development including the design of new tools and technologies for vaccine delivery have boosted optimism in the field about the prospects for the development of a safe and effective HIV vaccine. 
| Conclusion|| |
HIV has impacted the mankind as none so ever. The HIV/AIDS pandemic has taken toll of not only lives, but several nations' governance and social fabric. It threatens regional political and socio-economic stability.
The antiretroviral drugs have shown promising results but their role in preventive has to be explored in detail. Thereafter, the discovery of the most effective and safe vaccine will turn a new leaf in the history of HIV/AIDS.
Closing the door to HIV
Despite over 30 years of efforts, there is neither an therapeutic cure nor effective vaccine. An efficacy of 31.2% has been demonstrated by the Thai RV144 vaccine trial. However an effective vaccine will likely rely on a breakthrough discovery of immunogens to elicit broadly reactive neutralizing antibodies, which may still take longer time to achieve. In view of above there is a need of a hour to explore other prophylactic strategies. 
Recently, antiretroviral treatment as prevention is an exciting area of hope in HIV-1 research. Even if effective, various financial, political and social challenges hinder the implementation of such strategy in heavily affected regions particularly in developing countries where drug resistant viruses have already been found with growing incidence. Another area of challenge is activating latently infected cells for therapeutic cure. After the establishment of viral latency, it is greatly difficult to eradicate HIV-1. Therefore, it is necessary to investigate strategies that may close the door to HIV-1. 
| References|| |
|1.||Who | HIV/AIDS. Available from: http://www.who.int/mediacentre/factsheets/fs360/en/index.html. [Last accessed on 2012 Jun 20]. |
|2.||HIV vaccine development-WHO. Available from: http://www.indexmedicus.afro.who.int/iah/fulltext/vaccine-hiv.pdf. [Last accessed on 2012 Jun 20]. |
|3.||An AIDS vaccine is possible. Available from: www.iavi.org/./iavi_ what _you_ should_know_about_aids_vaccine. [Last accessed on 2012 Jun 20]. |
|4.||Idoko JA, Isa SO. HIV vaccine development. Ann Ibadan Postgrad Med 2005;3:19-25. |
|5.||Cottingham MG, Carroll MW. Recombinant MVA vaccines: Dispelling the myths. Vaccine 2013;31:4247-51. |
|6.||Buonaguro L, Tagliamonte M, Visciano ML, Tornesello ML, Buonaguro FM. Developments in virus-like particle-based vaccines for HIV. Expert Rev Vaccines 2013;12:119-27. |
|7.||HIV vaccines. Available from: http://www.iavi.org. [Last accessed on 2012 Jun 22]. |
|8.||Coplan PM, Gupta SB, Dubey SA, Pitisuttithum P, Nikas A, Mbewe B, et al. Cross-reactivity of anti-HIV-1 T cell immune responses among the major HIV-1 clades in HIV-1-positive individuals from 4 continents. J Infect Dis 2005;191:1427-34. |
|9.||Flynn NM, Forthal DN, Harro CD, Judson FN, Mayer KH, Para MF, et al. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J Infect Dis 2005;191:654-65. |
|10.||Pantaleo G, Koup RA. Correlates of immune protection in HIV-1 infection: What we know, what we don′t know, what we should know. Nat Med 2004;10:806-10. |
|11.||Lévy Y, Gahéry-Ségard H, Durier C, Lascaux AS, Goujard C, Meiffrédy V, et al. Immunological and virological efficacy of a therapeutic immunization combined with interleukin-2 in chronically HIV-1 infected patients. AIDS 2005;19:279-86. |
|12.||Lu W, Arraes LC, Ferreira WT, Andrieu JM. Therapeutic dendritic-cell vaccine for chronic HIV-1 infection. Nat Med 2004;10:1359-65. |
|13.||Poignard P, Sabbe R, Picchio GR, Wang M, Gulizia RJ, Katinger H, et al. Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo. Immunity 1999;10:431-8. |
|14.||Berman PW, Gregory TJ, Riddle L, Nakamura GR, Champe MA, Porter JP, et al. Protection of chimpanzees from infection by HIV-1 after vaccination with recombinant glycoprotein gp120 but not gp160. Nature 1990;345:622-5. |
|15.||Connor RI, Korber BT, Graham BS, Hahn BH, Ho DD, Walker BD, et al. Immunological and virological analyses of persons infected by human immunodeficiency virus type 1 while participating in trials of recombinant gp120 subunit vaccines. J Virol 1998;72:1552-76. |
|16.||Morgan C, Marthas M, Miller C, Duerr A, Cheng-Mayer C, Desrosiers R, et al. The use of nonhuman primate models in HIV vaccine development. PLoS Med 2008;5:e173. |
|17.||New vaccine could turn HIV into minor infection. Fox News dated 2011-09-29. Available from: http://www.foxnews.com/health/2011/09/29/new-vaccine-could- turn-hiv-into-minor-infection. [Last accessed on 2013 Oct 20]. |
|18.||Sekaly RP. The failed HIV Merck vaccine study: A step back or a launching point for future vaccine development? J Exp Med 2008;205:7-12. |
|19.||The HVTN 505 HIV Vaccine Regimen Study from National Institute of Allergy and Infectious Diseases, NIH USA. Available from: http://www.niaid.nih.gov/news/QA/Pages/HVTN505qa2013.aspx. [Last accessed on 2013 Oct 20]. |
|20.||Kang Y, Guo J, Chen Z. Closing the door to human immunodeficiency virus. Protein Cell 2013;4:86-102. |