This article is more than 5 years old. Information may no longer be current.
Vaccine necessary to eliminate global HIV/AIDS pandemic
Click Here to Manage Email Alerts
Although the current HIV/AIDS pandemic could theoretically be prevented through the appropriate use of pre-exposure prophylaxis and antiretroviral drugs, it is likely that a vaccine will be needed to eliminate the spread of the disease, according to an editorial published in JAMA.
“HIV is unique in that the body has a great deal of difficulty mounting an adequate response to the virus, which is unlike any other virus including measles, polio and smallpox,” Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, told Infectious Diseases in Children. “Although these viruses cause disease and sometimes death, the body ultimately provides a very good immune response that clears the virus and protects you from reinfection with the same virus. If we can create a vaccine that mimics natural [HIV] infection — as we have done successfully with many vaccines — we can really make a major impact.”
Additionally, the expense of this line of treatment and prevention for the 1.8 million people with newly acquired infections per year is considerable. Fauci cites an estimate set by The Joint United Nations Programme on HIV/AIDS (UNAIDS) in which the cost of adequate prevention and treatment in low- and middle-income countries would cost $350 billion between 2016 and 2030.
The author also noted a recent 7% decline in global government funding, highlighted in a study conducted by the Kaiser Family Foundation and UNAIDS, which leaves funding at its lowest level since 2010.
“Financially, it is a big burden to keep up with treating people and prevention modalities,” Fauci said. “When there are economic constraints in some countries, they do not abandon the funding of HIV, but they decrease it because of other priorities and constraints… HIV has been around a long time and has cost a lot of money.”
Although the need for a vaccine is understood, Fauci questions how effective the vaccine must be to slow or eliminate the spread of HIV; results from a large vaccine trial published in The New England Journal of Medicine demonstrated that vaccination was only 31% effective at preventing infection.
Fauci noted that although other vaccines intended to control or stop outbreaks have been significantly more effective, a 100% efficacy would not be probable because a protective response against HIV is difficult. This result, according to the author, warrants licensure of the vaccine. Additionally, modeling studies have indicated that the pandemic spread of HIV and millions of new infections could be prevented with a vaccine that demonstrates even 50% efficacy.
“I think that we are making progress. If this were any other infection, we would be aiming for 96%-98% efficacy,” Fauci said. “I do not think we are going to reach that goal, but a vaccine with 50%-55% efficacy plus the implementation of existing interventions could turn around the epidemic and end it.” – by Katherine Bortz
Disclosure: The author reports no relevant financial disclosures.
Perspective
Back to Top
Highly effective antiretroviral drugs have contributed immensely in both increasing the life expectancy of infected individuals and reducing the transmission of new HIV infections. However, a prophylactic HIV vaccine is of paramount importance to completely control the pandemic.
One of the major obstacles for HIV vaccine development is the enormous genetic variability of the virus that provides it multiple ways to evade human immune surveillance mechanisms. Interestingly, studies have revealed that a subset of humans can elicit broadly neutralizing antibody (bnAb) responses in natural HIV infection.
These bnAb responses target the surface envelope spike trimer (Env) and are highly effective against a wide range of viral isolates. Passive transfer of bnAbs into non-human primates provides complete protection against mucosal challenge with virus. Therefore, a prophylactic vaccine that can elicit bnAbs of sufficient potency and concentration will likely exhibit sterilizing HIV immunity in humans. However, thus far, the conventional vaccine approaches have failed to elicit bnAbs responses, in part due to unique genetic requirements of precursors encoding these bnAbs that reduce their frequency, hence hampering their targetability by vaccines.
A new approach — termed as ‘reverse vaccinology 2.0’ — essentially feeds molecular information derived from Env-bnAb interactions to guide immunogen design. In particular, these approaches seek to target the unique features of bnAb precursors with higher precision to increase their chances of being elicited in an immunization or vaccine setting.
One of the novel strategies in this approach utilizes VH-germline targeting of a CD4 binding site (CD4bs) bnAb precursor; the CD4bs region on Env engages the interaction of HIV with the CD4 receptor on host cells. This vaccine strategy involves activation of a bnAb precursor encoding B cell receptor with a germline-targeting immunogen, followed by boosting with more native-like Env molecules to shepherd Ab responses along bnAb developmental pathways.
Besides the CD4bs site, this approach has been expanded to other HIV bnAb epitopes and the early studies have yielded highly encouraging results. Some of these germline-targeting candidates are in the preclinical development phase, and are due to enter phase-I human trials next year. Ideally, coupling these precursor-targeting Env molecules with novel vaccine design platforms that mimic the native Env trimer structures will likely increase the probability of eliciting appropriate bnAb responses through vaccination.
The overall track for HIV vaccine development looks quite promising, however, given the complexity of bnAb epitopes on the virus and difficulties in targeting the rare bnAb precursors, it appears a single vaccine immunogen may not be sufficient, but rather a multi-stage vaccine approach would be more feasible. This will involve testing of multiple vaccine candidates using novel sequential and cocktail immunization strategies. Such an approach will presumably require manufacturing of multiple HIV vaccine immunogens, setting up of human clinical trials and an extensive pipeline for analysis of the immune responses.
Advances in current technologies to isolate single B cell transcripts, identify and trace developing B cell lineages using deep sequencing tools and the germinal center biology should facilitate the precise analysis of these vaccine responses. Additionally, the ease of looking at the molecular details of antibody-Env interactions through X-ray crystallography and electron microcopy technologies should facilitate iterative testing of these vaccines and strategies in humans.
Dennis R. Burton, PhD
Department of immunology and microbiology
International AIDS Vaccine Initiative
Neutralizing Antibody Center
>Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery
The Scripps Research Institute
Ragon Institute of Massachusetts General Hospital
Raiees Andrabi, PhD
Department of immunology and microbiology
International AIDS Vaccine Initiative
Neutralizing Antibody Center
Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery
The Scripps Research Institute
Click Here to Manage Email Alerts