When it comes to HIV vaccine development, the ultimate goal is the approval of a compound that prevents people from becoming infected with the virus. According to a review article in the May 17 issue of the New England Journal of Medicine, even if current top HIV vaccine candidates do not prevent infection, they may still prove beneficial by prolonging disease-free survival and reducing secondary viral transmission. Anthony Fauci, MD, Director of the National Institute of Allergy and Infectious Diseases (NIAID), and Margaret Johnston, PhD, Director of NIAID's Vaccine Research Program, argue that such a vaccine may still fit into a comprehensive HIV/AIDS prevention effort.
Vaccines typically work by mimicking the effects of natural exposure to a specific infection. Because of initial exposure, the immune system develops the ability to recognize the infection and can protect the human body against it if it reappears. HIV, however, has thwarted scientists' efforts thus far to develop a classic preventive vaccine for the virus because of its ability to integrate into target cells and evade clearance by the immune system. The interaction between HIV and the immune system is complex, and how different HIV-specific immune responses control infection is only partially understood.
Once HIV enters the body, it infects crucial CD4 cells, replicates, spreads throughout the body, and establishes HIV reservoirs in lymphatic tissues. Within weeks of exposure, virus levels peak and then decline to levels that may remain low for months or years. It is believed that CD8 cells – cytotoxic (killer) T-cells – are responsible for this reduction in HIV levels. However, their ability to continue to suppress the virus declines over time as the virus mutates and the immune system is progressively destroyed.
The infection of CD4 cells occurs very early in HIV disease, and virus persists indefinitely. While other viruses also reproduce at astonishing rates in the body, most do not establish a permanent reservoir of infected cells. The window of opportunity to prevent long-term HIV infection may close permanently once a pool of latently infected cells is in place, Drs. Johnston and Fauci note.
Early efforts to develop an HIV vaccine focused on "humoral immunity" – the production and maintenance of neutralizing antibodies that can attach to and eliminate free-floating virus, before it has a chance to establish infection inside immune system cells. Unfortunately, research has determined that the effectiveness of antibody vaccines is stymied because of the rapid genetic changes that occur in the HIV's outer envelope protein, which allow the virus to escape detection.
An improved understanding of how HIV causes disease has brought increased attention to the role that CD4 cells could play in an HIV vaccine designed to spark "cellular immunity" – the priming of the immune system to target HIV-infected cells, before they're able to produce multiple copies of the virus and establish permanent reservoirs in the body.
Numerous animal and human studies have confirmed how important cellular immunity is in the early and later stages of HIV infection, even though the virus is never completely eliminated.
Vaccines that induce strong cellular immune responses may have some benefits, write Drs. Johnston and Fauci. In animal models of HIV infection, CD4 cell vaccines have reportedly decreased the total amount of virus produced during early infection, caused a reduction in virus levels following the acute stage of infection, or produced some combination of these effects. In many of these animals, disease progression was also delayed.
Based on the scientific evidence, several questions remain, say Drs. Johnston and Fauci: Can a vaccine that does not prevent HIV infection but reduces virus levels and preserves a segment of uninfected CD4 cells from destruction benefit the immunized individual? Might people immunized with CD4 cell vaccines before HIV exposure remain disease-free for a prolonged period once they are infected?
Additionally, CD4 cell vaccines may reduce secondary HIV transmission if they can help the immune system keep viral replication at a very low level for a long time. Studies have suggested that people with high levels of virus – including those in the first few weeks or months of infection – are most likely to infect their sexual partners. A preventive vaccine given before exposure to HIV might stifle the initial burst of virus, better control viral load and potentially reduce that person's ability to infect other people, Drs. Johnston and Fauci assert.
Vaccines of this type present several complications, however. CD4 cell-mediated control of HIV infection may not stave off disease forever. Additional human studies would be needed to determine if the vaccine also reduces the spread of HIV. Finally, an HIV vaccine that delays – but does not completely prevent – disease could not stand alone as a preventive measure. According to Drs. Johnston and Fauci, the public health community would need to include it as part of a broader HIV prevention program, so that recipients would minimize, or ideally, not engage in high-risk behaviors.
Currently, several vaccines that induce primarily CD4 cell responses are in, or will soon enter, expanded human clinical trials to determine if they impact HIV infection. Researchers also continue to give high priority to creating an HIV vaccine that induces broadly neutralizing antibodies, which might prevent the establishment of HIV infection. Although rare, such antibodies do exist, giving hope to scientists that a vaccine to induce such antibodies can be designed.
Drs. Johnston and Fauci conclude that a vaccine that prevents HIV infection by clearing the virus before cells become latently infected remains the goal. In addition, they believe that even a vaccine that does not prevent infection could prove beneficial if it prolongs the disease-free period and possibly even reduces virus transmission. If such a vaccine is shown to be successful and is eventually licensed, it would need to be delivered as part of a comprehensive, multifaceted HIV prevention program.
Source:
Johnston MI, Fauci AS. An HIV vaccine – evolving concepts. N Engl J Med 356:2073-81, 2007.
