The third edition of the State of the World’s Vaccines and Immunization brought some good news about efforts toward immunizing children against vaccine-preventable diseases and the development of new vaccines, but also some dire warnings about how the global economic downturn might impede progress in immunization programs.

The report, issued in October by the World Bank, the World Health Organization (WHO), and the United Nations Children’s Fund (UNICEF), noted that there are now 106 million children receiving the required three doses of DPT (diphtheria-pertussis-tetanus) vaccine before their first birthday—a 74% increase in coverage since 2000. Despite this progress, 24 million children a year still fail to receive even a single dose of the DPT vaccine.

“This report is really a call to action aimed at everyone. We need to stick with it,” said Graeme Wheeler, managing director of operations at the World Bank, at an October 21 report launch in Washington, D.C. Wheeler said an estimated US$1 billion is needed annually to ensure that new and existing vaccines will be delivered to all children in 72 of the world’s poorest countries. The global economic downturn is causing concern that the United Nations’ Millennium Development Goal to reduce deaths among children under age five by 66% between 1990 and 2015 will not be met if countries are forced to curtail their immunization campaigns.

The report noted that continued investments will also be needed to accelerate the development of vaccines against tuberculosis, AIDS, and malaria, which are responsible for more than four million deaths a year, mainly in developing countries. There are currently about 80 vaccine candidates in the late stages of clinical testing—40 of them are aimed at diseases for which a vaccine does not yet exist. Of those, the malaria vaccine candidate known as RTS,S/AS01, which is being developed by GlaxoSmithKline Biologicals and is now being tested in a Phase III trial in Africa, was cited as a high-impact vaccine that was the furthest along in clinical testing.

Nearly a year after a quintet of researchers from the World Health Organization (WHO) published an article in The Lancet describing the results of a mathematical model that predicted that a combination of annual HIV testing and immediate antiretroviral (ARV) treatment could potentially end the AIDS epidemic in 50 years, scientists, public health officials, and community activists gathered November 2-4 to talk exclusively about the strategy dubbed test and treat (see VAX July 2009 Spotlight article, Test and Treat on Trial).

The WHO convened the meeting in Geneva, Switzerland, to stimulate discussion about the ethical implications, acceptability, and feasibility of implementing the test-and-treat approach in various populations. Although the strategy looks promising based on mathematical models, it has not yet been subjected to the rigors of a randomized, controlled clinical trial.

The experts who gathered in Geneva included Julio Montaner, president of the International AIDS Society, who is a vocal advocate of early initiation of ARV treatment and has been studying the impact that expansion of ARVs has had on lowering community viral load and HIV incidence in Vancouver, British Columbia. Community viral load reflects the mean viral load of a group of HIV-infected individuals. Montaner said a study that looked at the effect of expanding ARV treatment from 3,500 HIV-infected individuals to 5,000 in a community in Vancouver appears to have had an impact on transmission. “All I am prepared to say right now is that new HIV infection rates are going down,” said Montaner.

Next Spring, US researchers are hoping to launch a pilot study, known as HVTN 065, to evaluate the feasibility of implementing test and treat in Washington, D.C., which has the highest prevalence of HIV in the country, and the Bronx in New York City, which has the highest AIDS death rate of the city’s five boroughs due to the fact that so many HIV-infected individuals there are diagnosed late. The three-year study will occur in high-risk communities where poverty, racial discrimination, AIDS stigma, distrust of doctors, and other factors can be barriers to accessing medical care. Wafaa El-Sadr, director of the Center for Infectious Disease Epidemiologic Research at Columbia University’s Mailman School of Public Health, will be heading up the pilot study, which is being funded by the US National Institute of Allergy and Infectious Diseases (NIAID) and reflects a collaborative effort between NIAID, the US Centers for Disease Control and Prevention, and local health departments in the two cities.

El-Sadr said the goals of the study are to determine the best way to link HIV testing and treatment programs, to retain HIV-infected individuals in treatment programs, and to ensure individuals adhere to their daily ARV regimens.

“What I got from the [WHO] meeting was a collective commitment of the importance of continuing to expand access to treatment,” said El-Sadr. “Only about 40% of people who need treatment today can obtain it. We have a long way to go.”

Mark Harrington, an activist who heads the Treatment Action Group in New York City, said at the very least, test and treat may provide better linkage between prevention and treatment. “Care and treatment and prevention need to be done altogether.”

How can the recently conducted AIDS vaccine trial in Thailand help inform researchers about the types of immune responses that can provide protection against HIV?

A recently completed efficacy trial in Thailand, known as RV144, showed that two vaccine candidates administered sequentially in what is referred to as a prime-boost regimen could reduce the risk of HIV infection by 31.2% (see VAXOctober 2009 Spotlight article, Vaccine Research Gains Momentum). This trial provided the first evidence of efficacy for any AIDS vaccine candidate.

Vaccines work because they train the immune system to produce various types of immune cells and proteins, referred to as immune responses, against a specific virus or bacteria. A vaccine can induce many different types of immune responses, including antibodies (Y-shaped proteins that bind to viruses and prevent them from infecting cells), cellular immune responses (CD4+ and CD8+ T cells that orchestrate the killing of virus-infected cells), as well as natural or innate immune responses. For HIV, researchers do not yet know which types of immune responses are necessary for protection. While the vaccine candidates tested in RV144 only provided a modest efficacy, this trial provides scientists with the first opportunity in humans to try to figure out which immune responses induced by these candidates actually protected some of the volunteers against HIV infection. The specific immune responses that are responsible for protection are referred to as the immune correlates of protection (see VAX November 2006 and December 2006 Primers on Understanding Immune Correlates of Protection, Part I and II).

If the immune correlates of protection can be identified from RV144, it would be a significant boost for AIDS vaccine research. Scientists could then design AIDS vaccine candidates that induce these specific responses at higher levels, and thereby improve upon the modest efficacy seen in RV144. But identifying the correlates from this trial will not be an easy task. Overall, relatively few volunteers became HIV infected during RV144, so researchers have a limited pool of individuals in which to search for immune correlates.

The hunt

Researchers will begin the hunt for correlates by screening the thousands of blood and cell samples collected from volunteers during RV144 for different types of immune responses. Specifically, researchers will look closely at the samples taken from the 51 participants who received the vaccine candidates yet still became HIV infected through natural exposure to the virus. Samples from these volunteers will be compared to those from the 8,146 participants who received the vaccine candidates but did not get infected.

Because there are many more uninfected vaccinees than infected vaccinees, scientists will try to match each HIV-infected vaccinee with four to five who are uninfected and who share a similar demographic and genetic profile. Matching the samples as closely as possible in terms of gender, race, age, level of HIV risk, and genetic background will enable researchers to rule out the role these other factors may have played in the immune responses to the vaccine candidates.

Researchers will use multiple laboratory tests, or assays, to try to tease out if a specific immune response—including antibodies or cellular immune responses—occurred more frequently or at a higher level in vaccinated volunteers who did not acquire HIV compared to those who did. Although RV144 showed some efficacy in preventing acquisition of HIV, the prime-boost regimen did not appear to have any impact on the amount of virus circulating in the blood of individuals who became HIV infected despite vaccination. This result has led many researchers to assume that the modest level of protection was more likely due to antibody responses than cellular immune responses. Antibodies are the key to protection for most, if not all, existing vaccines. Still, researchers will carefully analyze all categories of immune responses in the hunt for correlates from RV144.

Limited samples

Scientists will have to carefully choose which assays to conduct because a limited number of specimens were collected during RV144. This trial was not designed to determine the correlates of protection. No samples were collected until after the six-month vaccination period, and researchers did not collect cell or tissue samples from mucosal sites at which sexual transmission of HIV occurs.

The search for correlates is also hampered by the fact that researchers do not know exactly when people were exposed to HIV and whether the HIV-uninfected vaccinees were even exposed to HIV at all.

Additional studies

There are also additional studies that can help identify the correlates of protection. One of these studies, known as RV152, is already ongoing. It involves the 51 individuals who became infected in RV144 despite vaccination. Information collected from these volunteers may shed light on the characteristics of the virus that infected these individuals. Investigators are also considering whether to conduct a smaller trial with the same prime-boost regimen that is designed specifically to try to determine the immune correlates.

Researchers may also be able to collect valuable clues from studies in nonhuman primates. If they can replicate the protection seen in RV144 in nonhuman primates, they could then use this model to try to identify the immune responses that are responsible for protection.