Modern assessments have revealed that the majority of successfully licensed vaccines protect through elicitation of protective antibodies [74–77]. It has been postulated that with our limited current knowledge on correlates of protection, induction of both humoral and cell-mediated immune responses is important to combat HIV-1 in the peripheral compartment and in the mucosal tissues, the entry point of the virus . These considerations led to develop vaccine strategies such as the concept of ‘prime-boost’ vaccination aiming at inducing and augmenting both types of responses [79–81]. Innate immune activation has also been a desired addition and new systems biology tools have become available to provide a framework to compare immune signatures that might predict subsequent HIV-1-specific immune responses induced by vaccines [82,83▪].
The vast majority of candidate vaccines were generally well tolerated, including those delivered using new modes (Biojector and electroporation) and routes (intravaginal, nasal, oral) of administration. Although there have been regional differences, background morbidity of healthy participants at a low risk for HIV-1 infection selected for phase I/II trials has not posed an obstacle to clinical trial conduct and interpretation . The RV144 prime-boost regimen tested for efficacy (ALVAC-HIV, vCP1521 and gp120 in alum, AIDSVAX B/E) exhibited a remarkable safety profile in more than 8000 Thai vaccinees . ALVAC-HIV (vCP1521) was also been found to be well tolerated in infants born to HIV-1-infected mothers .
Following the Step trial (HVTN 502) outcome in 2007, in which Ad5 vector-based vaccinees were at a higher risk of HIV acquisition than placebo recipients, concerns were raised about the use of new vectors, in particular adenovirus-based vectors. In individuals with pre-existing Ad5-specific neutralizing antibody (NAb) titres, a greater number of HIV-1 infections occurred in vaccinees. Posthoc multivariate analysis suggested that the greatest increased risk was in men who had pre-existing Ad5-NAb and were uncircumcised . The vaccine-associated risk waned with time from vaccination . The increased HIV-1 infection rate observed among uncircumcised men was not supported by a behavioural explanation . The presence of Ad5-NAb was not linked to the risk of HIV-1 acquisition among unvaccinated populations at an elevated risk of HIV-1 infection . Antivector immunity differed qualitatively in Ad5 seropositive participants who became HIV-infected compared with uninfected controls; Ad5 seropositive participants who later acquired HIV had lower neutralizing antibodies to capsid. Moreover, Ad35 seropositivity was decreased in HIV-infected individuals compared with uninfected controls, whereas seroprevalence for other serotypes including Ad14, Ad28 and Ad41 was similar in both groups . Given the unclear significance of these findings, close monitoring of such events is warranted in future efficacy trials with recombinant adenovirus vectors.
An increasing interest in potent adjuvants administered systemically or mucosally to bolster immune responses has introduced other safety concerns. Following administration of a polyvalent DNA prime-protein boost HIV-1 vaccine formulated with QS21, two individuals developed strong delayed-type hypersensitivity reactions with cutaneous leukocytoclastic vasculitis and Henoch-Schonlein purpura . Although such events are rare, safety and tolerability needs to be carefully monitored following the administration of adjuvanted proteins in prime-boost regimens.
Another concern, unrelated to safety, is the potential social harm that comes from vaccine-induced seropositivity (VISP) in uninfected vaccinees. The use of vaccines expressing several HIV-1 proteins, as well as HIV-1 envelope subunit proteins formulated with adjuvants, has led to an increasing proportion of vaccinated individuals testing HIV-1 positive with routine diagnostic tests. This has raised growing concern in communities targeted for HIV-1 vaccination and with health authorities regarding the differentiation of VISP from true HIV-1 infection . For example, more than 80% of volunteers vaccinated with an adjuvanted envelope subunit protein still tested HIV-1 positive 8 years postvaccination . Although western blot and nucleic acid tests may allow this differentiation, the development of cheaper and easier-to-run antibody-based diagnostic tests able to differentiate VISP from HIV-1 infection is actively pursued [93–95].
The Vax003 and Vax004 trials evaluated the efficacy of recombinant HIV-1 gp120 proteins. They have provided important insights into vaccine-elicited immune responses and the potential bar that needs to be overcome for further HIV-1 vaccine efficacy studies. In Vax004, higher NAb responses to an easy-to-neutralize virus (MN) corresponded with a lower risk of infection in the vaccine group. Evidence of low-level NAb responses against more-difficult-to-neutralize viruses suggests that level and breadth were not sufficient for protection . However, other studies reported that antibody-dependent cellular virus inhibition (ADCVI) corresponded with a decreased HIV-1 infection rate , suggesting that beneficial immune responses did not reach sufficient magnitude to impact the outcome of the trial. Host genetics may have also played a role in the vaccine outcome. Although there was no evidence of increased HIV acquisition in vaccinees relative to placebo recipients, there has been suggestion that the vaccine may have increased the likelihood of acquiring HIV-1 infection in low-behavioural risk individuals with the Fcγ receptor IIIa genotype .
RV144 is the only HIV-1 vaccine efficacy trial to date that has demonstrated vaccine efficacy, with a modest level of protection of 31% [96▪▪]. Humoral responses were the predominant immune response in this trial, along with vaccine-elicited CD4+ T-cell responses [97,98▪]. A case–control study showed that IgG antibodies to the V1/V2 region of HIV-1 gp120 correlated with a decreased risk of infection [99▪▪,100,101], whereas IgA antibodies to the envelope correlated with a decreased vaccine efficacy in the vaccine group.
Follow-up studies further supported the role of V2-specific immunity in vaccine efficacy with evidence of a virus sieve effect in infected vaccine recipients at this gp120 region [102▪▪]. In addition, mAbs generated from RV144 vaccine recipients targeted a critical residue in V2 (K169), thus providing evidence that vaccine-induced antibodies could potentially mediate a virus sieve effect. These V2-specific antibodies can mediate antibody-dependent cellular cytotoxicity (ADCC), neutralization and low-level virus capture [121,122]. These studies do not prove whether the V2 IgG response was a mechanistic or nonmechanistic correlate [123▪]. They however generate new hypotheses to test in further efficacy clinical trials; namely, is there a functional role for V2-specific IgG antibodies or are they merely a marker of another functional immune response?
The plasma IgA antibody combined with the lack of knowledge of whether mucosal immune responses were elicited by vaccination has led to renewed interest in understanding the different forms of IgA and their potentially protective functions. Several RV144 follow-up studies as well as new vaccine studies are now collecting mucosal samples to probe these questions and determine the functional properties of vaccine-elicited IgA responses. In RV144, in the presence of low vaccine-elicited IgA responses, either ADCC or NAb responses correlated with a decreased risk of infection. ADCC responses were predominantly directed to the C1 conformational region of gp120 [124–126], although other epitope specificities (i.e. V2) also contributed to the overall response . Another hypothesis is that C1 region Env-specific IgA could block C1-specific IgG effector function due to their ability to bind to different Fc receptors on effector cells. It was recently demonstrated that IgA antibodies elicited by RV144 could block C1 region specific IgG-mediated ADCC (via natural killer cells) . These findings indicate that the study of Fc receptor mediated antibody function will be important in the evaluation of HIV-1 vaccines. In addition, there is a remaining open question as to whether V2 antibodies might block the gp120–α4β7 interaction and contribute at least partially to the protective effect against HIV-1 sexual transmission .
Despite the 31% protective efficacy observed in RV144 and the lack of protection in Vax003, NAb responses were lower in RV144 than in Vax003 [98▪]. The interpretation of these findings between the two trials remains difficult, as the route of HIV-1 transmission (heterosexual vs. IDU) was radically different. In previous clinical studies, it was found that gp120 induced high levels of Env-specific IgG4 antibodies , whereas ALVAC (vCP1452) prime and gp120 MN in alum boost elicited lower IgG4 relative to IgG1 and IgG3 antibodies . Antigen-specific IgG3 antibodies have been associated with control of the pathogen and clinical protection in several infectious diseases [130–132]. A comparative study of IgG subclasses between RV144 and Vax003 may provide additional clues to mechanisms of vaccine protection.
One of the main objectives for future vaccines is to counter HIV-1 variability. Several groups are focused on designing novel envelope immunogens capable of inducing broadly NAb [135–138]. This work is being based on study of envelope structure and host–pathogen interactions aimed at guiding the immune response towards the vulnerable sites on the envelope. Improvement of existing envelope immunogens to elicit higher levels of V2 antibodies is an approach suggested by antigenicity studies of the envelope used in RV144. These studies demonstrated that certain epitopes were better exposed as a result of a non-HIV-1 sequence inserted into the HIV-1 envelope and likely led to the elicitation of antibody epitope specificities in RV144 [139▪]. Whether V2 antibodies elicited by various envelope immunogens are functional in a cross-clade manner and universal correlates of risk or just the ‘tree hiding the forest’ remains to be demonstrated. Vaccines utilizing a combination of consensus and transmitter-founder envelopes may be able to induce neutralizing responses with greater breadth and potency than single-envelope immunogens . Whether the induction of IgA-blocking ADCC is a potential ‘spine on the rose’, and how to overcome it, also remains to be explored.
Mucosal IgA responses are elicited in acute HIV-1 infection but are focused predominantly on gp41 (and not gp120) and decline rapidly after the acute phase . Several studies in nonhuman primates have reported the elicitation of mucosal immunity by different vaccine regimens (reviewed in ). Interestingly, a gp41-derived peptide formulated on virosomes protected macaques against simian human immunodeficiency virus challenge and elicited mucosal IgA and IgG antibodies in the protected animals . The same vaccine administered in humans via systemic and mucosal routes elicited limited IgG and IgA antibodies in mucosal secretions . Further clinical trials with mucosal sampling will provide additional insights in the ability of different vaccine regimens to elicit mucosal antibodies. Moreover, some emerging vaccine strategies aim at inducing long-lived memory B-cell responses.
Combination regimens using heterologous vectors in prime-boost and inserts aiming at broadening CD4+ and CD8+ T-cell responses such as mosaics  and conserved sequences  are promising avenues. Alternative vectors that might minimize or eliminate the presence of pre-existing antivector immunity  such as rare serotype human  and chimpanzee [148,149] adenovirus vectors as well as replication-competent vectors  are now in early clinical development (Table 3). It remains however uncertain how the recent outcomes of HVTN505 and HVTN503 may impact the use of adenovirus vectors in humans.
Significant efforts are currently focused on advancing efficacy trials in sub-Saharan Africa with an emphasis on South Africa, due to the ongoing devastating subtype C HIV-1 epidemic. The HIV-1 subtype A epidemic also remains rampant in East Africa [151–153], which will demand similar efforts in the future. Although heterosexual transmission predominates in sub-Saharan Africa , an epidemic in MSM is now expanding [155,156]. MSM will represent the predominant high-risk population for future HIV-1 vaccine efficacy trials in Asia [157–159]. The feasibility of efficacy testing in IDU is questionable due to the success of harm reduction programmes  with decreasing HIV-1 incidence. The identification of low–intermediate risk populations with predominant heterosexual transmission in Asia should however deserve heightened attention for the implementation of future efficacy trials .
Adaptive trial designs that would allow for the ongoing comparative evaluation of multiple vaccine concepts have been suggested as a way to inform immune correlates analysis and enhance the efficiency of efficacy evaluation of HIV-1 vaccine candidates . They may also help address the complexities of evaluating the efficacy of multiple HIV prevention measures in combination [163,164].
Preventive HIV-1 vaccine clinical development is at a critical juncture due to the identification of correlates of HIV-1 infection risk from RV144. These findings have opened new avenues of research that were previously unforeseen and only made possible through the conduct of large-scale efficacy trials, in-depth analysis of immune response with modern laboratory assays, detailed statistical analysis and modelling, interdisciplinary teams and strong international collaborations.
Papers of particular interest, published within the annual period of review, have been highlighted as:
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 514).
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91. Van Braeckel E, Koutsoukos M, Bourguignon P, et al. Vaccine-induced HIV seropositivity: a problem on the rise. J Clin Virol 2011; 50:334–337.
92. Silbermann B, Tod M, Desaint C, et al. Short communication: long-term persistence of vaccine-induced HIV seropositivity among healthy volunteers. AIDS Res Hum Retroviruses 2008; 24:1445–1448.
93. Khurana S, Needham J, Park S, et al. Novel approach for differential diagnosis of HIV infections in the face of vaccine-generated antibodies: utility for detection of diverse HIV-1 subtypes. J Acquir Immune Defic Syndr 2006; 43:304–312.
94. Cooper CJ, Metch B, Dragavon J, et al. Vaccine-induced HIV seropositivity/reactivity in noninfected HIV vaccine recipients. JAMA 2010; 304:275–283.
95. Penezina O, Clapham D, Collins J, et al. New HIV peptide-based immunoassay resolves vaccine-induced seropositivity in HIV vaccine (Phase III) trial participants. Retrovirology 2012; 9 (Suppl 2):P120.
96▪▪. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand. N Engl J Med 2009; 361:1–12.
A seminal trial (RV144) showing for the first time that an HIV vaccine regimen can confer protection against HIV acquisition.
97. de Souza MS, Ratto-Kim S, Chuenarom W, et al. The Thai phase III trial (RV144) vaccine regimen induces T cell responses that preferentially target epitopes within the V2 region of HIV-1 envelope. J Immunol 2012; 188:5166–5176.
98▪. Montefiori DC, Karnasuta C, Huang Y, et al. Magnitude and breadth of the neutralizing antibody response in the RV144 and Vax003 HIV-1 vaccine efficacy trials. J Infect Dis 2012; 206:431–441.
A comparative analysis of the neutralizing antibody response in two seminal antibody-based efficacy trials.
99▪▪. Haynes BF, Gilbert PB, McElrath MJ, et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med 2012; 366:1275–1286.
A seminal study (RV144) identifying for the first time correlates of risk (IgG V2 and IgA antibodies) for HIV acquisition.
100. Karasavvas N, Billings E, Rao M, et al. The Thai Phase III HIV type 1 vaccine trial (RV144) regimen induces antibodies that target conserved regions within the V2 loop of gp120. AIDS Res Hum Retroviruses 2012; 28:1444–1457.
101. Zolla-Pazner S, Decamp AC, Cardozo T, et al. Analysis of V2 antibody responses induced in vaccinees in the ALVAC/AIDSVAX HIV-1 vaccine efficacy trial. PLoS One 2013; 8:e53629.
102▪▪. Rolland M, Edlefsen PT, Larsen BB, et al. Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2. Nature 2012; 490:417–420.
A seminal study supporting the role of gp120 V2 in protection in RV144.
103. Gilbert PB, Berger JO, Stablein D, et al. Statistical interpretation of the RV144 HIV vaccine efficacy trial in Thailand: a case study for statistical issues in efficacy trials. J Infect Dis 2011; 203:969–975.
104▪. Robb ML, Rerks-Ngarm S, Nitayaphan S, et al. Risk behaviour and time as covariates for efficacy of the HIV vaccine regimen ALVAC-HIV (vCP1521) and AIDSVAX B/E: a posthoc analysis of the Thai phase 3 efficacy trial RV 144. Lancet Infect Dis 2012; 12:531–537.
A study demonstrating a greater vaccine benefit (efficacy) in low-risk individuals.
105. Paris R, Bejrachandra S, Thongcharoen P, et al. HLA class II restriction of HIV-1 clade-specific neutralizing antibody responses in ethnic Thai recipients of the RV144 prime-boost vaccine combination of ALVAC-HIV and AIDSVAX B/E. Vaccine 2012; 30:832–836.
106. Rerks-Ngarm S, Paris RM, Chunsutthiwat S, et al. Extended evaluation of the virologic, immunologic, and clinical course of volunteers who acquired HIV-1 infection in a phase III vaccine trial of ALVAC-HIV and AIDSVAX(R) B/E. J Infect Dis 2013; 207:1195–1205.
107▪▪. Buchbinder SP, Mehrotra DV, Duerr A, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 2008; 372:1881–1893.
The first efficacy trial of a T-cell-based vaccine that failed to confer protection.
108. Rolland M, Tovanabutra S, deCamp AC, et al. Genetic impact of vaccination on breakthrough HIV-1 sequences from the STEP trial. Nat Med 2011; 17:366–371.
109. McElrath MJ, De Rosa SC, Moodie Z, et al. HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis. Lancet 2008; 372:1894–1905.
110. O’Brien KL, Liu J, King SL, et al. Adenovirus-specific immunity after immunization with an Ad5 HIV-1 vaccine candidate in humans. Nat Med 2009; 15:873–875.
111. Gray GE, Allen M, Moodie Z, et al. Safety and efficacy of the HVTN 503/Phambili study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study. Lancet Infect Dis 2011; 11:507–515.
112. Cohen J. More woes for struggling HIV vaccine field. Science 2013; 340:667.
113. Pitisuttithum P, Gilbert P, Gurwith M, et al. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J Infect Dis 2006; 194:1661–1671.
114. Gilbert P, Wang M, Wrin T, et al. Magnitude and breadth of a nonprotective neutralizing antibody response in an efficacy trial of a candidate HIV-1 gp120 vaccine. J Infect Dis 2010; 202:595–605.
115. Forthal DN, Gilbert PB, Landucci G, et al. Recombinant gp120 vaccine-induced antibodies inhibit clinical strains of HIV-1 in the presence of Fc receptor-bearing effector cells and correlate inversely with HIV infection rate. J Immunol 2007; 178:6596–6603.
116. Forthal DN, Gabriel EE, Wang A, et al. Association of Fcγ receptor IIIa genotype with the rate of HIV infection after gp120 vaccination. Blood 2012; 120:2836–2842.
117. Flynn NM, Forthal DN, Harro CD, et al. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J Infect Dis 2005; 191:654–665.
118. Gilbert PB, Ackers ML, Berman PW, et al. HIV-1 virologic and immunologic progression and initiation of antiretroviral therapy among HIV-1-infected subjects in a trial of the efficacy of recombinant glycoprotein 120 vaccine. J Infect Dis 2005; 192:974–983.
119. Gilbert PB, Peterson ML, Follmann D, et al. Correlation between immunologic responses to a recombinant glycoprotein 120 vaccine and incidence of HIV-1 infection in a phase 3 HIV-1 preventive vaccine trial. J Infect Dis 2005; 191:666–677.
120. Schneider JA, Alam SA, Ackers M, et al. Mucosal HIV-binding antibody and neutralizing activity in high-risk HIV-uninfected female participants in a trial of HIV-vaccine efficacy. J Infect Dis 2007; 196:1637–1644.
121. Liao HX, Bonsignori M, Alam SM, et al. Vaccine induction of antibodies against a structurally heterogeneous site of immune pressure within HIV-1 envelope protein variable regions 1 and 2. Immunity 2013; 38:176–186.
122. Liu P, Yates NL, Shen X, et al. Infectious virion capture by HIV-1 gp120 specific IgG from RV144 vaccinees. J Virol 2013; Epub ahead of print.
123▪. Plotkin SA, Gilbert PB. Nomenclature for immune correlates of protection after vaccination. Clin Infect Dis 2012; 54:1615–1617.
A comprehensive review of the definition of immune correlates of protection.
124. Ferrari G, Pollara J, Kozink D, et al. An HIV-1 gp120 envelope human monoclonal antibody that recognizes a C1 conformational epitope mediates potent antibody-dependent cellular cytotoxicity (ADCC) activity and defines a common ADCC epitope in human HIV-1 serum. J Virol 2011; 85:7029–7036.
125. Bonsignori M, Pollara J, Moody MA, et al. Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial target multiple epitopes and preferentially use the VH1 gene family. J Virol 2012; 86:11521–11532.
126. Moody MA, Yates NL, Amos JD, et al. HIV-1 gp120 vaccine induces affinity maturation in both new and persistent antibody clonal lineages. J Virol 2012; 86:7496–7507.
127. Tomaras GD, Ferrari G, Shen X, et al. Vaccine induced plasma IgA specific for the C1-region of the HIV-1 envelope blocks binding and effector function of IgG. Proc Natl Acad Sci U S A 2013; Epub ahead of print.
128. Nakamura GR, Fonseca DP, O’Rourke SM, et al. Monoclonal antibodies to the V2 domain of MN-rgp120: fine mapping of epitopes and inhibition of α4β7 binding. PLoS One 2012; 7:e39045.
129. Gorse GJ, Patel GB, Mandava M, et al. MN and IIIB recombinant glycoprotein 120 vaccine-induced binding antibodies to native envelope glycoprotein of human immunodeficiency virus type 1 primary isolates. National Institute of Allergy and Infectious Disease Aids Vaccine Evaluation Group. AIDS Res Hum Retroviruses 1999; 15:921–930.
130. Banerjee K, Klasse PJ, Sanders RW, et al. IgG subclass profiles in infected HIV type 1 controllers and chronic progressors and in uninfected recipients of Env vaccines. AIDS Res Hum Retroviruses 2010; 26:445–458.
131. Roussilhon C, Oeuvray C, Müller-Graf C, et al. Long-term clinical protection from falciparum malaria is strongly associated with IgG3 antibodies to merozoite surface protein 3. PLoS Med 2007; 4:e320.
132. Kam YW, Simarmata D, Chow A, et al. Early appearance of neutralizing immunoglobulin G3 antibodies is associated with chikungunya virus clearance and long-term clinical protection. J Infect Dis 2012; 205:1147–1154.
133. Fitzgerald DW, Janes H, Robertson M, et al. An Ad5-vectored HIV-1 vaccine elicits cell-mediated immunity but does not affect disease progression in HIV-1-infected male subjects: results from a randomized placebo-controlled trial (the Step study). J Infect Dis 2011; 203:765–772.
134. Li F, Finnefrock AC, Dubey SA, et al. Mapping HIV-1 vaccine induced T-cell responses: bias towards less-conserved regions and potential impact on vaccine efficacy in the Step study. PLoS One 2011; 6:e20479.
135. Koff WC. HIV vaccine development: challenges and opportunities towards solving the HIV vaccine-neutralizing antibody problem. Vaccine 2012; 30:4310–4315.
136. Burton DR, Ahmed R, Barouch DH, et al. A blueprint for HIV vaccine discovery. Cell Host Microbe 2012; 12:396–407.
137. Haynes BF, Kelsoe G, Harrison SC, et al. B-cell lineage immunogen design in vaccine development with HIV-1 as a case study. Nat Biotechnol 2012; 30:423–433.
138. Benjelloun F, Lawrence P, Verrier B, et al. Role of human immunodeficiency virus type 1 envelope structure in the induction of broadly neutralizing antibodies. J Virol 2012; 86:13152–13163.
139▪. Alam SM, Liao HX, Tomaras GD, et al. Antigenicity and immunogenicity of RV144 vaccine AIDSVAX clade E envelope immunogen is enhanced by a gp120 N-terminal deletion. J Virol 2013; 87:1554–1568.
A study showing how to improve Env immunogen design based on the RV144 analysis of correlates of risk.
140. Liao HX, Tsao CY, Alam SM, et al. Antigenicity and immunogenicity of transmitted/founder, consensus and chronic envelope glycoproteins of human immunodeficiency virus type 1. J Virol 2013; 87:4185–4201.
141. Yates NL, Stacey AR, Nolen TL, et al. HIV-1 gp41 envelope IgA is frequently elicited after transmission but has an initial short response half-life. Mucosal Immunol 2013; Epub ahead of print.
142. Duerr A. Update on mucosal HIV vaccine vectors. Curr Opin HIV AIDS 2010; 5:397–403.
143. Bomsel M, Tudor D, Drillet AS, et al. Immunization with HIV-1 gp41 subunit virosomes induces mucosal antibodies protecting nonhuman primates against vaginal SHIV challenges. Immunity 2011; 34:269–280.
144. Barouch DH, O’Brien KL, Simmons NL, et al. Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys. Nat Med 2010; 16:319–323.
145. Letourneau S, Im EJ, Mashishi T, et al. Design and pre-clinical evaluation of a universal HIV-1 vaccine. PLoS One 2007; 2:e984.
146. Frahm N, DeCamp AC, Friedrich DP, et al. Human adenovirus-specific T cells modulate HIV-specific T cell responses to an Ad5-vectored HIV-1 vaccine. J Clin Invest 2012; 122:359–367.
147. Penaloza-MacMaster P, Provine NM, Ra J, et al. Alternative serotype adenovirus vaccine vectors elicit memory T cells with enhanced anamnestic capacity compared to Ad5 vectors. J Virol 2013; 87:1373–1384.
148. Sheehy SH, Duncan CJ, Elias SC, et al. ChAd63-MVA-vectored blood-stage malaria vaccines targeting MSP1 and AMA1: assessment of efficacy against mosquito bite challenge in humans. Mol Ther 2012; 20:2355–2368.
149. Dicks MD, Spencer AJ, Edwards NJ, et al. A novel chimpanzee adenovirus vector with low human seroprevalence: improved systems for vector derivation and comparative immunogenicity. PLoS One 2012; 7:e40385.
150. Excler JL, Parks CL, Ackland J, et al. Replicating viral vectors as HIV vaccines: summary report from the IAVI-sponsored satellite symposium at the AIDS vaccine 2009 conference. Biologicals 2010; 38:511–521.
151. Ruzagira E, Wandiembe S, Abaasa A, et al. Prevalence and incidence of HIV in a rural community-based HIV vaccine preparedness cohort in Masaka, Uganda. PLoS One 2011; 6:e20684.
152. Shaffer DN, Ngetich IK, Bautista CT, et al. HIV-1 incidence rates and risk factors in agricultural workers and dependents in rural Kenya: 36-month follow-up of the Kericho HIV cohort study. J Acquir Immune Defic Syndr 2010; 53:514–521.
153. Price MA, Rida W, Mwangome M, et al. Identifying at-risk populations in Kenya and South Africa: HIV incidence in cohorts of men who report sex with men, sex workers, and youth. J Acquir Immune Defic Syndr 2012; 59:185–193.
154. Mishra S, Steen R, Gerbase A, et al. Impact of high-risk sex and focused interventions in heterosexual HIV epidemics: a systematic review of mathematical models. PLoS One 2012; 7:e50691.
155. Smith AD, Tapsoba P, Peshu N, et al. Men who have sex with men and HIV/AIDS in sub-Saharan Africa. Lancet 2009; 374:416–422.
156. Sanders EJ, Okuku HS, Smith AD, et al. High HIV-1 incidence, correlates of HIV-1 acquisition, and high viral loads following seroconversion among MSM. AIDS 2013; 27:437–446.
157. Beyrer C, Baral SD, van Griensven F, et al. Global epidemiology of HIV infection in men who have sex with men. Lancet 2012; 380:367–377.
158. van Griensven F, de Lind van Wijngaarden JW. A review of the epidemiology of HIV infection and prevention responses among MSM in Asia. AIDS 2010; 24 (Suppl 3):S30–S40.
159. van Griensven F, Thienkrua W, McNicholl J, et al. Evidence of an explosive epidemic of HIV infection in a cohort of men who have sex with men in Bangkok, Thailand. AIDS 2012; Epub ahead of print.
160. Dutta A, Wirtz AL, Baral S, et al. Key harm reduction interventions and their impact on the reduction of risky behavior and HIV incidence among people who inject drugs in low-income and middle-income countries. Curr Opin HIV AIDS 2012; 7:362–368.
161. Nitayaphan S, Ngauy V, O’Connell R, Excler JL. HIV epidemic in Asia: optimizing and expanding vaccine development. Expert Rev Vaccines 2012; 11:805–819.
162. Corey L, Nabel GJ, Dieffenbach C, et al. HIV-1 vaccines and adaptive trial designs. Sci Transl Med 2011; 3:79ps13.
163. Padian NS, McCoy SI, Manian S, et al. Evaluation of large-scale combination HIV prevention programs: essential issues. J Acquir Immune Defic Syndr 2011; 58:e23–e28.
164. Cremin I, Alsallaq R, Dybul M, et al. The new role of antiretrovirals in combination HIV prevention: a mathematical modelling analysis. AIDS 2013; 27:447–458.