Will those hard-working humanized mice help get us to an AIDS vaccine? Scientists are sounding more optimistic.


New findings from an ongoing Phase III malaria vaccine trial in Africa suggest that the candidate, RTS,S, reduces the incidence of clinical malaria and severe malaria by a modest 31.3% and 36.6%, respectively, among children 6-12 weeks of age. Published online on Nov. 9 in the New England Journal of Medicine, the results nonetheless find that the efficacy of RTS,S was less than that reported last year for older children enrolled in the same trial (see VAX  Nov. 2011 Spotlight article, A Shot at Fighting Malaria). It also appears to be lower than  previously reported in a smaller Phase II trial. 

Mary Hamel, a medical epidemiologist at the US Centers for Disease Control and Prevention and a principal investigator at one of the trial’s clinical research centers in Kisumu, Kenya, said researchers should gain some clarity when data from all the sites where the study was conducted are released in the next year or two. “We may find that by pooling the data across the 11 trial sites, differences in vaccine efficacy by malaria transmission intensity were masked,” Hamel says. “Most malaria cases in this analysis were from areas of very high transmission. Efficacy in areas of low or moderate malaria transmission may be higher, consistent with the Phase II trial.” 

Developed and manufactured by GlaxoSmithKline (GSK) Biologicals, RTS,S contains a protein found on the surface of the P. falciparum sporozoite—the form of the parasite transmitted from mosquitoes to people—linked to hepatitis B vaccine antigen. It is formulated with AS01, an adjuvant manufactured by GSK.

The RTS,S candidate was co-administered with two licensed vaccines: a pentavalent vaccine against diphtheria, tetanus, pertussis, hepatitis B and Hemophilus influenzae type B, and a polio vaccine.  Scientists suggest that the co-administration of the licensed vaccines—including the Hep B antigen, which was effectively delivered twice—may have compromised the immune response to the RTS,S candidate. Hamel adds that infants have immature immune systems that respond less vigorously to vaccination, and that their responses might have been further compromised by antibodies against the sporozoites passed down by their mothers. Lower vaccine efficacy could also be associated with higher-transmission regions, but that will only be known when the site-specific analysis is completed.

The fate of RTS,S remains unclear. The PATH Malaria Vaccine Initiative, which financed most of the research with a $200 million grant from the Bill & Melinda Gates Foundation, hasn’t yet announced any decision. “The efficacy came back lower than we had hoped, but developing a vaccine against a parasite is a very hard thing to do,” said Bill Gates in a statement on PATH’s website. “The trial is continuing, and we look forward to getting more data to help determine whether and how to deploy this vaccine.” —Regina McEnery

Mark Dybul, a medical doctor and immunologist who helped create and then led the President’s Emergency Program for AIDS Relief (PEPFAR) for three years, will be heading up The Global Fund to Fight AIDS, Tuberculosis and Malaria in Geneva. 

Dybul’s appointment comes at a particularly rocky time for The Global Fund, a prolific fundraiser that has been grappling with both funding and management problems in recent years (see The Global Fund’s Uncertain FutureIAVI Report, Jan.-Feb. 2012).  Dybul replaces Michel Kazatchkine, who left the organization in early 2012, not long after The Global Fund’s board of directors appointed international banker Gabriel Jaramillo to the newly created position of general manager and put him in charge of day-to-day operations. 

Dybul was a staff clinician at the US National Institute of Allergy and Infectious Diseases when he joined a task force that led to the creation of PEPFAR in 2003. Since 2009, he has co-directed the Global Health Law Program at the O’Neill Institute for National and Global Health Law at Georgetown University. —Regina McEnery


How will the re-election of US President Barack Obama impact domestic and international AIDS spending and policies? Long before the bitter contest was settled on Nov. 6, the focus had already shifted to Jan. 1, when US $7 trillion worth of tax increases and automatic spending cuts over 10 years will begin to take effect unless Congress acts. Most economists agree that doing nothing will push the US economy over a so-called “fiscal cliff” and drive the country into another recession. But what specifically would that mean for AIDS spending, both on the ground and in the lab? With negotiations now underway in Washington and gridlocked US lawmakers trying to forge a compromise that has eluded them for two years, VAX science writer Regina McEnery asked the executive director of AVAC—a global HIV prevention group advocating for a vaccine—what he thinks a second Obama term likely means for the global AIDS agenda. The interview was conducted Nov. 9.

Has the outcome of the US election changed the dynamics of these budgetary talks? 

It’s a great question. I hope it changes something. It really comes down to—will the US government find a solution to the fiscal cliff by January. It is an incredibly important issue, one with huge importance for global health. If the US government goes into sequestration [across-the-board automatic spending cuts] it would have a staggeringly bad effect on both global health, and science and technology research and development. It could cut potentially 8% from the US National Institutes of Health’s budget, which has been flat-lined the last couple of years. In the case of PEPFAR [the US President’s Emergency Program for AIDS Relief], many countries have already gone through caps on treatment slots because resources are thinner. If we saw significant cuts to foreign aid, there would be even fewer people in treatment. It will become harder to help people adhere to treatment and suppress viral load.

Do you think this crisis can be averted? 

My hope, and I tend to be an optimist given the re-election of Obama and the Democratic-controlled Senate, is that they all seem to get it. Obviously the current business-as-usual has to change. We have to get the US deficit under control. But while hard cuts have to be made, sequestration is the worst way to do it. Jobs would be lost, progress would be rolled back.

What role are AIDS advocates playing during these budget talks?

A lot of advocacy has to be around making sure people see what the impact of sequestration will be. And I think we also need to make sure we keep in view the long arc of what we are trying to accomplish, to show the hard-fought investments that have been made. Despite some setbacks, we have seen advances over the last several years in R&D and global health. It took a long time to create these programs. Once you turn the tap off, and have to lay people off and close down programs, to restart [those programs] even a year later is far more complicated.

What should be the goals and objectives of the blueprint to get us to an AIDS-free generation, which US Secretary of State Hillary Clinton called for at the International AIDS Conference this summer? 

The office of the Global AIDS Coordinator is working on the blueprint and we expect it by World AIDS Day [Dec. 1]. Our eyes are on that blueprint. Will it be just a lot of flowery language or will it provide us with a clear, feasible and ambitious program with achievable targets that enable us to make very hard decisions that are aligned with the [scientific] evidence? More importantly will it lay out a management system that quantifies quarterly and annually what we need to do? If we need to, say, perform four million circumcisions in certain countries, by 2014, we can’t wait until 2015 to make sure if we hit that number. In 2003, Jim Kim, then director of the World Health Organization’s AIDS Program launched the 3 by 5 initiative [3 million on ARVs by 2005]. People said he was crazy and the target would not be met, and while those people were right about the target, setting those targets and using them to measure against progress was pivotal.

Should a goal of this blueprint be a vaccine? 

Absolutely. Along with short-term goals, the blueprint has got to include a long-term, end-game strategy for today and for the next 20 years that emphasizes the need for a vaccine and I would argue investment in cure research. There has to be an R&D agenda for new technologies and interventions while scaling up existing interventions.

It looks like the Affordable Care Act [ACA] is here to stay. How will the law impact HIV services?
We have been a treating society, not a preventing society. One of the best things [in the law] is that prevention is now part of the health care system and that means more access to things like HIV testing and preventive services. And more people will also have access to care. The challenge right now is: How do you implement [the ACA]? Many states are in a waiting situation. We all need to be keeping our eye on that.

The fiscal cliff aside, PEPFAR is also up for reauthorization next year. Where does it stand? 

We need to make sure [PEPFAR] is funded robustly. Advocates are pushing for reauthorization and for it to be included in the blueprint to make sure PEPFAR gets implemented. There is also a concept you are hearing more and more called country ownership. Countries will need to step up and own their [AIDS] programs.

And what about the $63 billion Global Health Initiative?

PEPFAR was supposed to be the foundation of the Global Health Initiative. Since its rollout questions have been raised about how much money should be spent on AIDS, should we not be focusing on other diseases. Yet if one looks at the last decade, the AIDS treatment response fundamentally changed the way health systems were funded and implemented around the world in a great way. We have to be sure, even as we look to the more comprehensive approaches, that we don’t let things slip back to the pre-PEPFAR days. To me, whether you are talking about PEPFAR, the Global Health Initiative, the Global Fund [to fight AIDS, Tuberculosis and Malaria], the single biggest issue in 2013 is global leadership. We know Sec. Clinton has had a huge role to play, but she has said she will not serve in Obama’s second term. Who will be her replacement? Her successor has very large shoes to fill.


What are the major challenges that AIDS researchers have faced in developing DNA vaccines and how are recent advances helping them overcome these challenges?

Many common viral vaccines have been made by either killing a virus of interest or weakening it so that it doesn’t cause disease. When people are immunized with such preparations, they mount an immune response that subsequently protects them from pathogenic strains of the targeted virus. Unfortunately, using a weakened or attenuated version of HIV to stimulate protective immunity remains off limits to developers of AIDS vaccines. HIV mutates very rapidly, changing its genetic makeup dramatically even within one infected individual. Researchers therefore worry that an attenuated HIV could mutate and regain its ability to cause disease. Using a killed version of HIV in a vaccine candidate, meanwhile, is impractical because it is difficult to prove that the virus is completely inactivated. Further, such vaccines have failed to protect monkeys against simian immunodeficiency virus (SIV, the monkey equivalent of HIV).

These concerns have led scientists to look for better and safer methods for creating AIDS vaccine candidates. One such alternative is DNA vaccination, in which genes from a pathogen of interest are injected into people to generate a protective immune response. Essentially, DNA HIV vaccines are composed of harmless pieces of HIV’s own DNA that have been pasted into circular pieces of DNA known as plasmids, which infect bacteria in the wild and have long been used to express genes in laboratories. 

After an engineered and purified DNA plasmid is injected into a person—usually with a gene gun into skin and muscle—it is passively taken up by cells. Those cells then use their own protein-making machinery to produce the HIV proteins encoded by the plasmid. This usually results in the activation of the cellular immune response, which targets virally infected cells. But DNA vaccines can also be engineered to elicit antibody responses, which can block the viral invasion of cells and have historically played a central role in vaccine immunization (see Feb. 2004 Primeron Understanding the Immune System, Part 1 and Mar. 2004 Primer on Understanding the Immune System, Part II).

When DNA vaccination was first proposed in the early 1990s, the preclinical data seemed promising. Scientists had found that mice inoculated subcutaneously with genes encoding human growth hormone developed antibodies against that protein. Further, DNA vaccine candidates were even then relatively easy to make and stable at room temperature. Researchers were therefore attracted to this strategy. It meant that such vaccine candidates could be produced relatively rapidly and cheaply in large quantities and would, further, suit the needs of the developing world, where refrigeration capacity is often limited and transportation difficult. 

But DNA vaccine candidates also presented some challenges. Most prominently, they triggered relatively weak immune responses because plasmids are not very efficiently taken up by cells. Producing stable forms of engineered plasmid DNA also proved to be harder and more expensive than researchers had expected. These setbacks dampened enthusiasm for DNA vaccines, not just against HIV but other pathogens as well. In fact, no DNA vaccine has yet been licensed to prevent a human disease.

New tools improve responses

In recent years, however, technological advances have revitalized the field of DNA vaccination. One new tool that has contributed to its resurgence is electroporation (EP), a vaccine delivery technology that induces temporary pores in the membranes of muscle or skin cells so that they can more easily take plasmids. Small hand-held EP devices these days often include a needle to inject the vaccine and thin wires that administer short electrical pulses during vaccine delivery. 

Initially developed in the 1970s, EP has been refined and tested in a growing number of human studies since the early 1990s. In recent years, EP devices have been tweaked to cause less pain and deliver plasmids more efficiently, and continue to be tested in HIV vaccine trials.

Adjuvants, which stimulate the immune response to vaccines, are also being used to improve DNA-based vaccine candidates. Many licensed vaccines, such as the influenza vaccine, are formulated with chemical adjuvants. But as researchers’ understanding of the immune system and its factors has grown in sophistication, entirely novel adjuvants and methods for their co-delivery are being tried out in clinical trials. Rather than just co-formulate their vaccine candidates with adjuvants, for example, AIDS vaccine developers have designed DNA plasmids to carry genes for proteins that are potent boosters of cellular immune responses. One such protein, Interleukin 12, is naturally produced by dendritic cells—which have long been known to play a central role in vaccine immunization. Clinical trials are now testing DNA vaccine candidates that are delivered via electroporation along with the gene for IL-12.

Researchers have also tweaked the plasmids used to make DNA vaccines so that human cells can express more of the HIV antigens they encode, and so trigger more robust immune responses. One way they do this is by including in the plasmids promotors—DNA sequences that initiate the reading of genes for protein production—that are more effective at driving gene expression. 

Vaccine developers also enhance immune responses by using DNA candidates as a prime, and then boosting the response it provokes with another agent—such as the canarypox viral-vector vaccine candidate that was used in the RV144 trial in Thailand. Any such regimen is referred to as a heterologous prime-boost. The DNA used as the prime focuses the immune response on the vaccine candidate inserts, perhaps with the help of an adjuvant. The subsequent boost enhances the primed response. 

Together, new technologies and such traditional immunization strategies have contributed to a resurgence in DNA vaccine development.