JAMA – July 12, 2016 [Special Focus – HIV, Vaccines, Prevention]

July 12, 2016, Vol 316, No. 2

Viewpoint | July 12, 2016
An HIV Vaccine -Mapping Uncharted Territory FREE
Anthony S. Fauci, MD1
JAMA. 2016;316(2):143-144. doi:10.1001/jama.2016.7538.
Scaling up access to antiretroviral therapy and proven approaches to HIV prevention potentially could control the HIV/AIDS pandemic and reduce it to a low level of endemicity. However, a safe and effective HIV vaccine would help reach this goal more quickly and in a more sustained way.

The scientific quest for an HIV vaccine spans nearly 3 decades and has taken multiple pathways, including attempts to induce antibody responses, T-cell responses, or combinations of both. These efforts have included human efficacy trials of monomeric HIV envelope glycoproteins, vectors containing inserts of HIV genes expressing envelope and other viral proteins, and prime-boost regimens that combine both approaches.1

So far, the only HIV vaccine efficacy trial to show promise was the RV144 trial conducted in Thailand. For immunogens, this study used a canarypox vector expressing HIV genes as a prime, followed by 2 booster injections of a recombinant HIV envelope glycoprotein.2 The trial resulted in a very modest vaccine efficacy of 31%. Neither broadly neutralizing antibodies nor cytolytic CD8+ T-cell responses were associated with protection against infection. Rather, IgG antibodies against the V1V2 region of the HIV envelope protein were associated with reduced infection.3 Efforts are now under way to improve on the results of RV144 in a southern African population by using multiple boosts, modified vectors, and adjuvants.

In addition to the follow-up of RV144, major HIV vaccine efforts have been launched in another direction: inducing broadly neutralizing antibodies (bNAbs) that can neutralize a wide range of HIV variants and hence afford protection against the rapidly mutating virus.1

Neutralizing antibodies have long been considered the “gold standard” of protection for vaccines against viruses because of the consistent observation that essentially all viral infections induce neutralizing antibodies, typically within days of infection. If the patient survives the infection, neutralizing antibodies usually clear the virus and provide lifelong protection against subsequent exposure to the same virus. Thus, the proof of concept for the development of a vaccine for most viruses is already provided by natural infection, and vaccines that optimally mimic natural infection have been the norm.

Not so for an HIV vaccine. The antigens presented by HIV to the immune system in natural infection do not elicit an adequate immune response to clear a virus that integrates,4 as evidenced by the lack of documented immune-mediated clearance of the virus by any known HIV-infected individual. HIV elicits high levels of broadly neutralizing antibodies in only a fraction of patients, usually only after a period of 2 or more years.1 With HIV, proving it is even possible for a vaccine to induce such antibodies is being explored by vaccinologists who are working in previously uncharted territory.

In their pursuit of bNAbs against HIV, scientists have used technologies that never before had been required (or even considered) in developing vaccines for other pathogens.1 These include x-ray crystallography and more recently cryoelectron microscopy to determine the native conformation of HIV envelope; novel cellular cloning technologies to isolate the rare B cells that recognize HIV envelope epitopes; high-throughput deep sequencing of B-cell genes and the unprecedented interrogation of the B-cell lineage to identify unmutated, germline B cells that might bind to known HIV envelope epitopes; and approaches to “steering” the B-cell lineage to make bNAbs.

The leading candidate for an HIV vaccine immunogen that elicits bNAbs is the viral envelope glycoprotein in forms that present native envelope epitopes. The HIV envelope is inherently unstable; in natural infection it preferentially presents to the immune system epitopes that elicit antibodies that are not broadly neutralizing, and that would be inadequate in the context of a vaccine. Investigators have determined that non-neutralizing antibodies bind to structures displayed on the unstable envelope, whereas several bNAbs bind readily to structural elements expressed on an experimentally stabilized envelope trimer.

A reasonable assumption, then, would be that the stable HIV envelope trimer may serve as a component of an immunogen to engage the relevant HIV-specific B-cell repertoire and induce it to produce bNAbs. Using the structural biological tools of x-ray crystallography and most recently the elegant technique of cryoelectron microscopy, investigators have successfully identified the near-native structure of the envelope trimer and stabilized it by insertion of various mutations.5 However, that was only the first step. The next step is to engage (if possible) the unmutated, naive B cells that give rise to bNAbs. These B cells are rare, occurring as infrequently as 1 in 2.5 million cells.

A major challenge encountered by scientists is that certain HIV envelope epitopes to which naturally occurring bNAbs bind do not bind to any identifiable germline B cell. Another potential obstacle was observed in an animal model: vaccination with a stable envelope trimer induced autologous neutralizing antibodies but not bNAbs.6 Thus, the process of generating bNAbs did not achieve its intended goal.
Subsequent efforts have been intensively directed at overcoming the inability to get past autologous neutralizing antibodies and proceed to production of bNAbs, notably with a new strategy that has been called “B-cell lineage design.” This concept was exemplified by a fortuitous experiment of nature. In an acute HIV infection study with extremely close follow-up of study participants, a patient who became infected was studied from the very earliest point after acute HIV infection.7 Scientists closely monitored the evolution of the antibody response and how the virus mutated to escape that evolving immune response. What unfolded was a back-and-forth of mutating virus escaping the immune response and the immune response evolving to keep up with the mutating virus. At the end of more than 2 years, the virus had coaxed along the immune response to produce antibodies that were broadly neutralizing for a wide variety of archived HIV isolates. However, the patient still had virus that was not neutralized by the resulting bNAb.7 Nonetheless, this observation fortified the concept of “B-cell lineage design” and the pursuit of sequential stimulation of the B-cell lineage with slightly different immunogens that mimic the evolving and mutating virus. Clearly, this strategy is quite different from the classic approach in vaccinology of priming and boosting with essentially the same antigen. The technically complex and intense interrogation and engagement of the B-cell limb of the immune response has provided some of the most elegant scientific studies performed in the context of vaccine development. However, it is unclear whether the application of this approach will be feasible in the context of a vaccine for millions of people.

Indeed, the field of HIV vaccinology is in uncharted territory. If efforts in developing an HIV vaccine based on the induction of bNAbs are successful, this achievement will represent the most elegant and complex scientific approach toward any vaccine in history. In contrast, if unsuccessful, this experience will be recorded as the most highly sophisticated and scientifically elegant proof that the development of such a vaccine is impossible. Hopefully, the former and not the latter will be true.

Marking Time in the Global HIV/AIDS Pandemic FREE
Gerald Friedland, MD
…The IAS conference returns to Durban in July 2016, and presents a unique opportunity to review the 15 years since the landmark 2000 meeting. It will document the current status of the global pandemic and consider and plan the future goals and strategies for the global struggle against HIV/AIDS.

Remarkably, a historic turn of events has been achieved during the past 15 years, representing perhaps one of the greatest scientific, medical, and public health realignment of resources between rich and poor. Resources and expertise have been shifted toward those poorer communities and populations in the world where the epidemic has reached full force. Research support has increased and has demonstrated the importance of new treatment and prevention tools and strategies of global benefit. Local governments and international agencies such as the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization; the Global Fund on AIDS, Tuberculosis, and Malaria; the US President’s Emergency Plan for AIDS Relief; other nations’ programs; nongovernmental organizations; academic institutions; private philanthropy; and other efforts have been assembled to meaningfully counteract the global pandemic, providing evidence-based prevention and treatment and attempting to reduce many of the issues of equity and health disparities at the pandemic’s core.

New HIV infections have declined by 35% since 2000 and the number of people accessing ART globally has doubled every 3 to 4 years, increasing exponentially from an estimated 690 000 in 2000 (the vast majority in the developed world) to 3 million in 2007 and to 17 million people at the end of 2015.3 Of these, 10.3 million (61%) were in sub-Saharan Africa. Global coverage of ART increased from less than 5% in 2000 to 46% at the end of 2015.4 South Africa has the largest HIV epidemic in the world, with an estimated 6.3 million people living with HIV in 2013, but now has initiated ART for nearly 3.4 million people living with HIV/AIDS, more than any other country in the world.4 Studies have demonstrated a restoration of life expectancy on a population level, similar to what had been seen in the United States after the introduction of ART5 and population-based declines in HIV transmission were shown as ART was rolled out.

The past 15 years also have seen a large increase in effective HIV prevention tools, including condoms, harm reduction, male circumcision, and vaginal microbicides as well as structural (ie, policies, laws, institutional, and administrative approaches) and community-based approaches. The availability and use of ART remains the most potent tool, both as treatment and prevention of new infections in maternal to child transmission, HIV discordant partners,6 and, most recently, as preexposure prophylaxis.7 All of these strategies, including those that address fundamental human rights, must be used in combination to provide the greatest benefit. With these effective tools and strategies, is the world now on the cusp of another epochal change in the pandemic?

The power of combining treatment and prevention has resulted in the formulation by UNAIDS of the 90-90-90 strategy to be accomplished by 2020.8 This is defined as 90% of all people living with HIV will know their HIV status, 90% of these will receive sustained ART, and 90% of these will have viral suppression. Further extending this to 2030 with a strategy of 95-95-95 is estimated to avert an additional 17.6 million HIV infections and 10.8 million AIDS-related deaths between 2016 and 2030,8 and carries the expectation that the pandemic will be eliminated (ie, the global prevalence of HIV will be reduced to a negligible amount and no longer represent a global public health threat).

However, enormous challenges remain in reaching these goals. They include the difficulties of engaging key populations with the treatment and prevention benefits, the fragility and weakness of the health care systems needed for their delivery, the fact that neither a vaccine nor cure is expected within this time frame and ART remains a lifelong therapy with challenges of linkage to care, medication adherence, and loss to follow-up all impinging on sustained viral suppression. Continued stigma and intractable human rights challenges, comorbidities, such as tuberculosis (the leading cause of mortality in people living with HIV/AIDS), and increasingly drug-resistant tuberculosis, all pose major hurdles.

In addition, it is unclear whether the costs to local and international communities will be bearable, estimated as increasing from the current $19 billion per year to $36 billion per year, and whether political will can be sustained over time.9 A central question at the 2016 IAS conference will be if, with the now-available powerful prevention and treatment tools, these goals and strategies are realistic and attainable or, at best, only aspirational.

The accomplishments of the past 15 years were similarly deemed unrealistic and aspirational, and perhaps such a triumph of global success will be repeated and the HIV/AIDS pandemic not only can be reversed, but contained. The 2016 IAS meeting in Durban will again provide a view of the present and a glimpse into the future of the still disastrous and volatile HIV/AIDS pandemic.

Condomless Sex With Virologically Suppressed HIV-Infected Individuals: How Safe Is It? FREE
Eric S. Daar, MD; Katya Corado, MD

Antiretrovirals for HIV Treatment and Prevention: The Challenges of Success FREE
Kenneth H. Mayer, MD; Douglas S. Krakower, MD

Visions for an AIDS-Free Generation: Red Ribbons of Hope FREE
Preeti N. Malani, MD, MSJ


Original Investigations
Effect of Patient Navigation With or Without Financial Incentives on Viral Suppression Among Hospitalized Patients With HIV Infection and Substance Use: A Randomized Clinical Trial FREE
Lisa R. Metsch, PhD; Daniel J. Feaster, PhD; Lauren Gooden, PhD; Tim Matheson, PhD; Maxine Stitzer, PhD; Moupali Das, MD; Mamta K. Jain, MD; Allan E. Rodriguez, MD; Wendy S. Armstrong, MD; Gregory M. Lucas, MD, PhD; Ank E. Nijhawan, MD; Mari-Lynn Drainoni, PhD; Patricia Herrera, MD; Pamela Vergara-Rodriguez, MD; Jeffrey M. Jacobson, MD; Michael J. Mugavero, MD; Meg Sullivan, MD; Eric S. Daar, MD; Deborah K. McMahon, MD; David C. Ferris, MD; Robert Lindblad, MD; Paul VanVeldhuisen, PhD; Neal Oden, PhD; Pedro C. Castellón, MPH; Susan Tross, PhD; Louise F. Haynes, MSW; Antoine Douaihy, MD; James L. Sorensen, PhD; David S. Metzger, PhD; Raul N. Mandler, MD; Grant N. Colfax, MD; Carlos del Rio, MD
Includes: Supplemental Content

Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy FREE
Alison J. Rodger, MD; Valentina Cambiano, PhD; Tina Bruun, RN; Pietro Vernazza, MD; Simon Collins; Jan van Lunzen, PhD; Giulio Maria Corbelli; Vicente Estrada, MD; Anna Maria Geretti, MD; Apostolos Beloukas, PhD; David Asboe, FRCP; Pompeyo Viciana, MD; Félix Gutiérrez, MD; Bonaventura Clotet, PhD; Christian Pradier, MD; Jan Gerstoft, MD; Rainer Weber, MD; Katarina Westling, MD; Gilles Wandeler, MD; Jan M. Prins, PhD; Armin Rieger, MD; Marcel Stoeckle, MD; Tim Kümmerle, PhD; Teresa Bini, MD; Adriana Ammassari, MD; Richard Gilson, MD; Ivanka Krznaric, PhD; Matti Ristola, PhD; Robert Zangerle, MD; Pia Handberg, RN; Antonio Antela, PhD; Sris Allan, FRCP; Andrew N. Phillips, PhD; Jens Lundgren, MD; for the PARTNER Study Group
Includes: CME, Supplemental Content
Editorial: Condomless Sex With Virologically Suppressed HIV-Infected Individuals;
Eric S. Daar, MD; Katya Corado, MD

Association of Medical Male Circumcision and Antiretroviral Therapy Scale-up With Community HIV Incidence in Rakai, Uganda FREE
Xiangrong Kong, PhD; Godfrey Kigozi, MB, ChB, PhD; Joseph Ssekasanvu, MS; Fred Nalugoda, PhD; Gertrude Nakigozi, MD, MPH; Anthony Ndyanabo, MSc; Tom Lutalo, MS; Steven J. Reynolds, MD, MPH; Robert Ssekubugu, MHS; Joseph Kagaayi, MB, ChB, PhD; Eva Bugos, BS; Larry W. Chang, MD, MPH; Pilgrim Nanlesta, PhD; Grabowski Mary, PhD; Amanda Berman, MSPH, MPhil; Thomas C. Quinn, MD; David Serwadda, MB, ChB, MMed, MPH; Maria J. Wawer, MD, MSH; Ronald H. Gray, MD, MSc
Includes: CME, Supplemental Content


Special Communication
Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society–USA Panel FREE
Huldrych F. Günthard, MD; Michael S. Saag, MD; Constance A. Benson, MD; Carlos del Rio, MD; Joseph J. Eron, MD; Joel E. Gallant, MD, MPH; Jennifer F. Hoy, MBBS, FRACP; Michael J. Mugavero, MD, MHSc; Paul E. Sax, MD; Melanie A. Thompson, MD; Rajesh T. Gandhi, MD; Raphael J. Landovitz, MD; Davey M. Smith, MD; Donna M. Jacobsen, BS; Paul A. Volberding, MD
Includes: CME, Supplemental Content
Editorial: Antiretrovirals for HIV Treatment and Prevention; Kenneth H. Mayer, MD; Douglas S. Krakower, MD


From the JAMA Network
Reaching High-Risk Patients for HIV Preexposure Prophylaxis FREE
James Riddell IV, MD; Jonathan A. Cohn, MD, MS