HIV/AIDS vaccines for Africa: scientific opportunities, challenges and strategies

More than decades have already elapsed since human immunodeficiency virus (HIV) was identified as the causative agent of acquired immunodeficiency syndrome (AIDS). The HIV has since spread to all parts of the world with devastating effects. In sub-saharan Africa, the HIV/AIDS epidemic has reached unprecedented proportions. Safe, effective and affordable HIV/AIDS vaccines for Africans are therefore urgently needed to contain this public health problem. Although, there are challenges, there are also scientific opportunities and strategies that can be exploited in the development of HIV/AIDS vaccines for Africa. The recent RV144 Phase III trial in Thailand has demonstrated that it is possible to develop a vaccine that can potentially elicit modest protective immunity against HIV infection. The main objective of this review is to outline the key scientific opportunities, challenges and strategies in HIV/AIDS vaccine development in Africa.


Introduction
Since the human immunodeficiency virus (HIV) was previously identified as the etiologic agent for acquired immunodeficiency syndrome (AIDS) more than three decades ago, the virus has spread to almost all parts of the world [1]. Globally, more than 34 The recent Thailand's RV144 phase-III trial has shown that it is possible to develop a vaccine that can induce some protective immune responses against HIV acquisition [3].  [36]. The CD4+ T cells of mucosal lymphoid tissues are also the targets of HIV throughout infection, leading to their depletion [37]. Mucosal plasma cells synthesize secretory immunoglobulin A (IgA) that has Page number not for citation purposes 4 the potential to neutralize HIV [38]. Mucosal surfaces are rich in immune cells such as dendritic cells, macrophages, CD4+ and CD8+ T cells which can play important roles in provoking immunity to a variety of pathogens including HIV [39]. Studies have demonstrated the presence of SIV-and HIV-specific CD8+ T cell responses in the genital tracts of infected macaques [40]. Inducing humoral, CD8+ and CD4+ T cell responses at mucosal surfaces with vaccines can potentially prevent or control HIV replication in the mucosal lymphoid tissue. One of the key advantages of mucosal vaccination against HIV is that mucosal immunity protects systemic infection, whereas systemic immunity poorly protects against mucosal infection [41]. The other advantage of mucosal vaccination is that antigenic exposure at one mucosal site activates B and T cells to emigrate and home to other mucosal surfaces, thereby conferring protection at these sites [42]. Protective vaccine-induced mucosal immunity against HIV has been demonstrated in animal models [43]. Therefore the challenge is to develop HIV vaccines for Africa that can induce both B and T cell responses in mucosal tissues.

Immune correlates of HIV protection in Africa
To date, the exact immune correlates of protection against natural protection against simian AIDS disease in monkeys [45,46].
Although CD8+ T cell and neutralizing antibodies are considered important for HIV protection or control of infection, the RV144 trial has demonstrated that non-neutralizing antibodies are also crucial [3]. Non-neutralizing antibodies can mediate antibody-dependent cellular cytotoxicity (ADCC), thereby protecting against HIV infection [47]. ADCC is important because it is associated with reduced HIV/AIDS diseases progression and prevention of cell-to-cell spread by the virus [48]. However, the rise of ADCC-escape HIV variants can be a scientific challenge to HIV/AIDS vaccine development [49].
Another key challenge is that antibodies mediated via complement system or Fc receptors can unfortunately facilitate the infectivity of the HIV [50]. Currently, there are no good animal models to test HIV/AIDS vaccines. Chimpanzees and macaques are most commonly used to study the HIV pathogenesis as well as vaccines [58]. Mice are also used in pre-clinical evaluation of vaccines, but results in mice do not normally predict what will be found in humans. The use of monkey or baboon primate models in studying HIV/AIDS vaccines has also its drawbacks. Data generated from mouse, monkey or baboon models do not normally translate to what will be found in human clinical trials. Humanized mice can also be used in testing HIV/AIDS vaccines, but they do not normally elicit strong immune responses [59].
Bantu-speaking African populations of Sub-Saharan Africa are highly diverse genetically [60]. The high prevalence of high-risk exposed

Scientific strategies for HIV/AIDS vaccine development for Africa
To date, there is no licensed HIV/AIDS vaccine for Africa. Several rational and empirical strategies to HIV vaccine development have so far failed dismally. However, a variety of these strategies need to be refined if we are to develop potential vaccine candidates for Africa. It has been a classical approach to use inactivated viruses as vaccines. It is possible to inactivate HIV and this strategy has been explored [64,65]. Although the inactivated HIV vaccine candidates may be safe for use, even in immunocompromised people, the strategy is not advocated for due to poor immunogenicity elicited by these vaccines. Such HIV vaccines would not be very helpful for Africa, given their poor immunogenicity. The great challenge is to generate inactivated vaccines that are highly immunogenic in Africans. It is easy to genetically attenuate viruses such as HIV Recombinant plasmids, when used as DNA vaccines induce immune responses specific to the antigen genes carried [72]. Most HIV DNA vaccines have been shown to be safe and to induce protective immune responses in animal models [73,74]. Induction of both CD8+ CTL and humoral immune responses were demonstrated in animals primed with gp120 DNA vaccine and boosted with gp120 subunit vaccine [75]. A number of candidate DNA vaccines for HIV-1 have already been developed and some tested in Africa for immunogenicity [76][77][78]. Such vaccines are likely to be useful in Africa since they induce strong immune responses especially if they are used in prime-boost strategies. Recombinant live viruses can be exploited as vaccine vectors for heterologous antigens [79,80]. The key advantage of viral vectors is that they can generate very strong antigen-specific CD8+ and CD4+ T cell as well as humoral immune responses [79][80][81]. Effective anti-HIV immunity, sometimes protective, has been observed in a number of animal studies in which vectors such as adenovirus, alphavirus, sendai virus, herpes simplex virus, human rhinovirus and polio virus were used to express HIV antigens [82][83][84][85][86]. Recombinant viral vectors therefore seem to offer great opportunities for vaccine development for Africans because of their ability to induce strong HIV-specific immune responses.
Recombinant bacteria can also be used to deliver heterologous antigens to the host's immune system [87]. Their potential use as candidate HIV vaccine vectors to deliver either HIV antigens or HIV DNA vaccines is currently being increasingly studied. Recombinant Bacillus Calmette-Guerin (BCG) expressing HIV antigens has been shown to induce antigen-specific immune responses in vaccinated animals [88]. BCG is generally a good vaccine vector for HIV/AIDS because of a number of reasons such as its known safety record [89]. Another attractive bacterial vaccine vector for HIV/AIDS is Listeria monocytogenes [90]. The key advantage of Listeria as a vaccine vector is that it replicates in the cytosol, thereby inducing both strong CD8+ and CD4+ T cell responses. Shigella is also an attractive vector that is capable of replicating in the cytosol thereby inducing strong cellular immune responses [91].
Attenuated Shigella strains have already been successfully used to deliver HIV DNA vaccines, resulting in induction of HIV-specific CD8+ T responses [92]. Recombinant Salmonella has also a great potential as a vaccine vector for HIV [93][94][95]. Therefore, recombinant bacterial vaccine vectors can be harnessed in the development of HIV/AIDS vaccines for Africa.
Candidate HIV/AIDS vaccines for Africa can be used in prime-boost strategies in order to improve their potency and effectiveness. In these strategies, one vaccine is used to prime the immune system and the second vaccine is used to boost the response [96,97]