VAX August 2008

Vol. 06, No. 08 - August 2008


Researchers gathered at the International AIDS Conference focused on long-term efforts to control the spread of HIV


The AIDS Vaccine Blueprint 2008, IAVI’s biennial report on the state of AIDS vaccine research and development and a roadmap for the field, was released at the XVII International AIDS Conference in Mexico City, August 3-8. It issues several challenges to AIDS vaccine researchers and outlines interim goals toward overcoming many of the obstacles impeding vaccine development, as well as milestones by which the field can measure its progress.
The Blueprint, which IAVI has been producing since 1998, strikes a different theme and tone than two years ago when more than two dozen AIDS vaccine candidates were moving through the pipeline, including Merck’s cellular immunity-based vaccine, known as MRKAd5, which many researchers regarded as the most promising.

Merck and the US National Institute of Allergy and Infectious Diseases stopped immunizations in the Phase IIb test-of-concept trial of this candidate last September after it failed to provide any protection against HIV infection. “Two years ago, we all thought we had a signal of hope from Merck,” said Seth Berkley, the founder and CEO of IAVI. “What has happened is we’ve learned a lot about the science.”

Because most of the AIDS vaccine candidates currently in clinical trials employ strategies similar to MRKAd5, the IAVIBlueprint urges stakeholders to “review their portfolios and drop candidates considered to have a low probability of success.”

IAVI suggests that the resources be spent instead on research efforts to develop a more diverse clinical pipeline of AIDS vaccine candidates that can induce both cellular immune responses and antibodies against HIV (see VAX July 2008 Special Issue on Understanding the Immune System and AIDS Vaccine Strategies).

Other recommendations in the Blueprint include establishing incentives to enhance innovation in AIDS vaccine discovery, and training the next generation of researchers. “Science is not a straight line,” said Alan Bernstein, president of the Global HIV Vaccine Enterprise, commenting about the recent setbacks in the AIDS vaccine field. “It’s clear after 25 years that we are on a long journey.” —Regina McEnery


US President George Bush recently signed into law a revised version of the President’s Emergency Plan for AIDS Relief (PEPFAR) authorizing US$48 billion in funding over the next five years to expand existing HIV/AIDS prevention, treatment, and care efforts worldwide. The original five-year, $15 billion plan, which has supported the provision of life-saving antiretroviral (ARV) treatment for approximately 1.7 million HIV-infected people, was due to expire in September. 

The revised version more than doubles the amount of funding for HIV/AIDS prevention, treatment, and care programs, and also authorizes $9 billion in funding for malaria and tuberculosis programs.

A section of the new PEPFAR bill also contains provisions related specifically to facilitating the development of vaccines, including those against HIV/AIDS, tuberculosis, and malaria. The US President is required to report to Congress within one year on a strategy for accelerating the development of these vaccines, including details on creation of economic incentives for research, development, and manufacture, as well as the efforts taken by the US to support clinical trials of vaccines in developing countries and to prepare these countries for the introduction of new vaccines. —Jonathan Grund, contributing writer


What are the implications of the genetic diversity of HIV for AIDS vaccine development?
Over the past century, scientists have assembled an impressive arsenal of vaccines to combat germs. Such vaccines have helped eradicate deadly scourges like smallpox and also shield millions of people each year from contracting the flu. 
Influenza A and B viruses, which are responsible for seasonal flu epidemics, are constantly changing and evolving as they circulate throughout the population. This is a survival mechanism for viruses. Like many vaccines, those against influenza work by inducing antibodies—Y-shaped proteins that bind to viruses and prevent them from infecting human cells—against the virus that can effectively neutralize it (see VAX July 2008 Special IssueUnderstanding the Immune System and AIDS Vaccine Strategies. An accumulation of changes or mutations at the site on the virus where these antibodies bind results in the formation of new strains of the virus that can effectively evade these antibodies, and therefore continue circulating within the population.

The amount of variation between strains of the same virus differs greatly. Influenza viruses change or mutate rapidly, forming new strains each year, which is why previously vaccinated individuals must get an annual flu shot to be protected. Vaccine developers study the mutation patterns of the virus and predict which strain will most likely be in circulation in a given season, and then update the influenza vaccine each year so that it will ideally protect against the predominantly circulating strain.

But compared to HIV, influenza’s mutation rate is remarkably slow. The genetic variation of HIV in a single infected individual is about the same as the yearly genetic variation of influenza within the entire human population. Of all human viruses, only the hepatitis C virus mutates more rapidly than HIV.

The incredible genetic variation of HIV occurs because the virus reproduces or replicates so rapidly once inside a human. In a single HIV-infected person, between one billion and 10 billion HIV particles are produced every day. HIV makes several mistakes as a result of this rapid-fire replication rate. These mistakes are like a typing error—hitting the wrong key and therefore changing the spelling of a word. HIV’s mistakes result in changes in its genetic sequence (see VAX July 2006 Primer on Understanding HIV Clades). Each change in the genetic sequence of the virus results in a unique version of the virus in an HIV-infected person, which in turn contributes to the extreme genetic variation of HIV globally. This variation could represent a significant challenge to AIDS vaccine researchers.

Sequencing technologies

Researchers have extensively studied the genetic variation of HIV in an attempt to inform AIDS vaccine design. Genetic sequencing, a process by which researchers can break down the virus into its genetic building blocks, has enabled scientists to distinguish different versions of HIV and classify them into different subtypes or clades. More efficient sequencing software has also begun to expose critical changes in the dynamics of HIV’s evolution. With the help of more sensitive sequencing technologies, scientists can now better understand the full diversity of HIV that is currently in circulation, including low-frequency variants undetected by older sequencing methods. These hard-to-detect variants are also important to consider when designing AIDS vaccine candidates.

In recent years, researchers have also begun employing advanced genetic sequencing methods to mine areas of vulnerability in HIV’s genome. One area of vulnerability are the sections of the virus that don’t vary much between different clades, so-called constant regions. These areas are important targets for vaccine researchers who are trying to develop vaccine candidates that would provide broad protection against the majority of HIV variants in circulation. Another area of vulnerability is the specific location on the virus where antibodies bind. Knowing the genetic sequence of the virus at the point where the antibody binds can help researchers identify the best immunogens—harmless pieces of HIV that are inserted into vaccine candidates in the hope of inducing an immune response against the virus. Researchers are also honing in on mutations that occur very early in the course of HIV infection.

Learning from trials

It is still unclear to what extent the genetic variation of HIV will matter in the context of AIDS vaccine development. Some AIDS vaccine candidates have included HIV immunogens from several clades to try to induce broad protection against several different clades of HIV, while others have included immunogens from a single HIV clade.

Researchers typically test AIDS vaccine candidates in geographical areas where the predominantly circulating clade of HIV matches the clade of the immunogens in the vaccine candidate. For example, the recently conducted STEP trial of Merck’s MRKAd5 vaccine candidate, which contained clade B HIV immunogens, was conducted in countries where the predominant virus in circulation was HIV clade B. However, in a companion trial to the STEP study, known as Phambili, researchers were testing this MRKAd5 candidate with clade B HIV immunogens in South Africa, where clade C HIV is predominantly circulating. Immunizations in this trial were stopped ahead of schedule after results from the STEP trial showed that the candidate did not provide any protection against HIV infection.

To determine if genetic variation played a role in MRKAd5’s inability to protect, researchers are carefully studying samples from the volunteers in the STEP trial who became HIV infected through natural exposure to the virus despite receiving MRKAd5. By analyzing the genetic sequence of HIV that infected these individuals, researchers can determine how different it was genetically from the immunogens that were included in MRKAd5. If the genetic sequence of the infecting virus and the immunogens are vastly different, researchers may determine that this played a role in the failure of the vaccine candidate to protect against HIV infection.