More than 60 million people have been infected with the human immunodeficiency virus since the beginning of the HIV/AIDS pandemic, and 2.7 million new HIV infections occurred in 2007 alone. Cumulative deaths associated with HIV infection number more than 25 million, with 2.0 million occurring in 2007.
In the United States, more than 560,000 people with HIV/AIDS have died. More than 56,000 new HIV infections occur annually. Approximately 1.1 million people are living with the virus. Recently, we learned that at least 3 percent of all adults and adolescents in Washington are infected with HIV, a prevalence rate approaching that of developing countries. Among African-American males in the nation’s capital, the number of infections is more than twice as high.
Since the Washington Department of Health issued the report on HIV and AIDS cases, I’ve been asked repeatedly: “Why do we not yet have an AIDS vaccine?” A safe and efficacious HIV vaccine would be a powerful tool to control the pandemic, but success in this area has been elusive despite more than 20 years of research.
It’s a very reasonable query, given the extraordinary successes in vaccine development for other serious diseases over the years. Highly effective vaccines have been developed for many other viral diseases, including polio, measles, mumps, rubella, hepatitis A, hepatitis B, influenza, rabies, varicella, human papillomavirus, rotavirus, yellow fever and Japanese encephalitis. One viral infection — smallpox — has been completely eradicated from the human population.
Many vaccines also are available to prevent important bacterial diseases, including pertussis (whooping cough), Haemophilus influenzae type b (Hib) disease, diphtheria, tetanus, typhoid, anthrax, cholera, meningitis and pneumonia. These vaccines have benefited hundreds of millions of people, averting suffering and premature death.
Nature assists vaccine
The developers of each of these vaccines all enjoyed the advantage of having a so-called “proof of concept” — a relatively reliable predictor of their vaccine’s likelihood of success. For each of these infections, the body can mount an effective response against the pathogen, even in the absence of a vaccine. Although these viral and bacterial diseases may cause considerable suffering and other consequences, including death, the vast majority of infected individuals recovers spontaneously and, ultimately, clears the virus or bacterium from their bodies.
Following natural infection, patients develop immunity that protects them from disease if they are exposed again to the same pathogen. This protective immunity is usually complete and often lifelong. Thus, nature assists the vaccine scientist by proving that the body can mount a durable, protective immune response following infection.
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A vaccine is designed to fool the body into thinking that it is infected. Vaccines usually contain a killed or weakened pathogen or a specific component of the pathogen, none of which can cause disease. The body then mounts a protective immune response against this harmless product and becomes prepared to eliminate subsequent threats by the same pathogen. This vaccine-induced preparation, referred to as immunological “memory,” enables the body to respond very rapidly upon re-exposure to the real pathogen, well before it can inflict damage that results in symptomatic illness or death.
Historically, vaccine development and evaluation began with the discovery, definition, and growth of the specific virus or bacterium that causes a disease, followed by a choice of vaccine approach (for example, live-weakened or killed, or a subcomponent of the pathogen). Since vaccine scientists knew that the body could mount an effective immune response against the live pathogen (nature’s proof of concept), they took an approach in which the most promising formulations were moved in a step-wise fashion into clinical testing.
The first attempts at developing an AIDS vaccine were guided in large part by this classical, trial-and-error approach even though scientists were not sure if a protective immune response to HIV was even possible. But because of the successful history of the classical approach and because of the seriousness of the global HIV pandemic, a few products were advanced to large-scale efficacy trials in the hope that they would be at least partially successful and help guide improvements in vaccine design. At worst, the scientific community would gather important information that would inform future efforts.
Unfortunately, this classical approach to vaccine development has not been successful in the quest for an HIV vaccine.
Relentless progression
HIV infection has never provided scientists with a proof of concept of predictable protection, which historically has been the guiding principle for successful vaccine development. Not a single individual is known to have spontaneously eradicated the virus following documented, established infection. In the vast majority of individuals not receiving antiretroviral therapy, the progression of HIV disease is relentless despite measurable, but apparently not completely adequate, HIV-specific immune responses.
The inadequacy of the HIV-specific immune response likely is due to several factors: notably the ability of HIV to establish latency, allowing it to “hide” in host cells and elude immune surveillance; the extraordinary diversity and mutability of the virus; the capacity of the virus to avoid a protective immune response by masking more conserved components of the virus; and the ability of HIV to destroy or cause the dysfunction of critical immune system cells.
Since natural infection has not provided us with the proof of concept for the development of an effective HIV vaccine, that task has been left to the research community. Unlike classical vaccinologists, HIV vaccine scientists must learn how to prompt the human body to produce a protective immune response that is superior to that elicited by natural infection. This has required a shift in the balance of effort from the empirical development and large-scale testing of candidate vaccines to the discovery of the mysteries of the interaction of HIV and the body’s immune system. In the shift of this balance, certain fundamental unanswered questions must be addressed in the discovery process before additional large clinical trials are warranted.
No ‘grace period’ with HIV
Paramount among these knowledge gaps is the need for a better understanding of the events early in HIV infection, beginning at the places where the virus enters the body. Following primary infection, the virus rapidly establishes itself in lymphoid tissues that are rich in vulnerable target cells for the virus. Wide dissemination of virus throughout the body occurs, and a viral reservoir with a latent component is rapidly established, likely within days.
This brief window of opportunity for intervention by a vaccine-induced immune response — likely measured in only a few days — contrasts with other viral diseases, notably poliomyelitis. Polio virus replicates for several days before it reaches its target cells in the central nervous system, that is, specific cells in the spinal cord. With polio, immediate neutralization of the virus upon its initial entry into the gut is not necessary; the immune response elicited by prior vaccination has several days to block the virus before it reaches its target organ.
Unfortunately, we do not have such a “grace period” with HIV, so we must devise a vaccine that elicits an immune response that acts quickly to destroy the virus or learn how to extend the “grace period.” Very rarely, an individual will develop antibodies that efficiently neutralize HIV, so this is at least theoretically possible. A major issue, however, will be to design a vaccine that induces these antibodies in a high percentage of people. This has been unsuccessful thus far.
Determining the atomic structure of the viral targets of these antibodies and understanding why these antibodies are not rapidly made in response to infection are critical in designing a vaccine that induces them. Another important goal is to determine the potential role of the innate immune system, a primitive but important arm of the body’s immune response, in an individual’s response to HIV, and to alter these early innate responses to better protect the body at the most frequent points of entry of the virus — that is, the mucosal surfaces of the genital tract.
If successful, manipulating the innate immune system might alter the course of infection, perhaps widening the window of opportunity for viral eradication before HIV establishes an intractable reservoir of virus.
Better understanding of all the earliest events of infection might also lead to other strategies that extend the “grace period” and allow the immune system time to more effectively respond. These and other questions will be answered only with creative thinking and experimentation, across many scientific disciplines, including those not traditionally associated with vaccine development.
Broader approach to prevention
Finally, understanding how some HIV infected individuals, the so-called “elite controllers” who are able to keep the virus in check for years to decades may provide a different sort of “proof of concept”. Perhaps the best that we can achieve is the best that nature has already done. Although developing a vaccine capable of preventing infection is the ultimate goal, development of a vaccine that enables the recipient to control infection for years to decades would delay the need to initiate antiretroviral therapy and potentially even reduce secondary transmission to others.
Since it is possible that an HIV vaccine alone will never fully prevent HIV infection the way smallpox or polio vaccines can, our efforts in HIV vaccinology must be part of a broader approach toward HIV prevention that includes the delivery of proven methods such as HIV testing and counseling, education and behavior modification, the use of condoms, the treatment and prevention of drug and alcohol abuse, syringe exchange programs, antiretroviral drugs to prevent mother-to-child HIV transmission, and medically supervised adult male circumcision.
Of note, new means of preventing HIV infection, such as topical microbicide gels to prevent sexual transmission of HIV and antiretroviral therapy (ART) as pre-exposure prophylaxis for individuals at high risk of HIV infection, are in advanced testing.
However, in a world where many vulnerable people have few encounters with medical or public health personnel and thus have limited access to HIV prevention services, a vaccine remains our best hope of controlling HIV.
Despite many scientific obstacles, and despite a lack of easily transferable lessons from classical vaccinology, the development of an HIV vaccine must remain at the top of the global health research agenda. The obstacles to success are scientific obstacles, and I am cautiously optimistic that we will overcome these obstacles with scientific solutions, so there is no longer a need to ask the question: “Why do we not yet have an AIDS vaccine?”
Immunologist Dr. Anthony Fauci is an internationally-known AIDS researcher and head of the national Institute of Allergy and Infectious Disease
