By Regina McEnery

In some ways, vaccine development has never looked more promising. A report released last year by the World Health Organization (WHO), the World Bank, and the United Nations Children’s Fund (UNICEF), declared that the last 10 years were the most productive ever in the history of vaccine development. Then, in January, at the World Economic Forum’s annual meeting in Davos, Switzerland, the Bill & Melinda Gates Foundation announced they were committing US$10 billion over 10 years to fund the research and development of new vaccines, and distribution of existing vaccines to people in the world’s poorest countries.

US President Barack Obama and his administration have also placed renewed emphasis on vaccine development. In a memo circulated in May, the Obama administration mentioned “seeking and then scaling up potential game-changers, such as vaccines,” as a way to solve longstanding challenges such as poverty.

While global health organizations and many public health researchers say vaccines are one of the most cost-effective ways of saving children’s lives and reducing poverty, the WHO estimates that only about 18% of the $6 billion annual global vaccine market is spent in developing countries, a point underscored at the 13th Annual Conference on Vaccine Research, which took place in Bethesda, Maryland from April 26-28.

The 400 researchers and public health workers who gathered at the meeting, which was organized by the National Foundation for Infectious Diseases, emphasized how difficult vaccine discovery and distribution can be. Vaccines typically take many years and a hefty investment of between $200 million and $500 million to develop, noted Don Francis, founder of the nonprofit organization Global Solutions for Infectious Diseases, during his keynote speech. And even when vaccines do get licensed, it can take decades until the disease is eradicated because of the logistical difficulties and expenses involved in distributing vaccines on a global scale. Although the first polio vaccine was licensed in 1955, it took 36 years for the virus to be eradicated in North America, and 50 years for it to be eradicated in all but four countries where it is still endemic, Francis noted.

Despite these obstacles, vaccine researchers are increasingly focusing on the link between poverty and disease, and the conference opened with an array of talks about the vital role human and animal vaccines can play in reducing poverty and in strengthening economic and political security, particularly in developing countries.

One area of focus is scaling up distribution of the recently licensed vaccines against rotavirus, which causes diarrheal disease, and pneumococcal bacteria, which cause pneumonia, in developing countries, where the death rate from these infections is highest. There is also more attention being given to an array of 13 so-called neglected tropical diseases (NTDs) that cause about 530,000 deaths annually and afflict about one billion of the world’s poorest people.

A number of scientists at the recent vaccine conference are hoping the emphasis on vaccines as a way to combat poverty will translate into increased funding for vaccine research and development. Though NTDs receive much less treatment and prevention funding than HIV/AIDS, tuberculosis, and malaria, they have devastating consequences on maternal and child health, and may increase susceptibility to HIV/AIDS and malaria or worsen disease progression in those already infected.

“NTDs impair intellectual and physical development in children, cause adverse pregnancy outcomes, and reduce worker productivity,” said Peter Hotez, chairman of microbiology, immunology, and tropical medicine at George Washington University Medical Center in Washington, DC.

A number of vaccine candidates against NTDs, so-called anti-poverty vaccines, are in the clinical pipeline. Hotez, who also heads up The Sabin Vaccine Institute, said they are hoping to soon begin a Phase IIb test-of-concept trial in Brazil of a vaccine candidate against hookworm, a parasitic worm that lives in the small intestine and infects about 576 million people, mostly in developing countries. Hookworm infection typically occurs when the larvae from hookworm eggs penetrate a person’s skin. The larvae eventually latch onto the intestinal wall, where they mature into adult hookworms and produce more eggs. Hookworm infection can cause, most seriously, anemia and iron deficiency due to severe blood loss. Prolonged, untreated hookworm infections can also result in mental retardation.

The Sabin Institute is also hoping to begin clinical trials of a vaccine candidate against schistosomiasis, another parasitic disease which infects approximately 207 million people worldwide, most of them in Africa. Both the Sabin Institute and the Institut Pasteur in France are developing vaccines against two different parasites that trigger schistosomiasis. The vaccines would be used along with drug treatment to reduce or delay disease progression.

Schistosomiasis is referred to as snail fever because the parasitic worms that spread the disease live in snails. People become infected when they come in contact with fresh water contaminated by the parasites that the snails excrete. The worms grow inside a person’s blood vessels and produce eggs, which then travel to the intestines or bladder. Like hookworm, repeated bouts of schistosomiasis can cause anemia and malnutrition. In rare instances, the eggs can be found in the brain or spinal cord, causing brain damage and paralysis.

More effort is also being given to control of foot-and-mouth disease, a highly contagious disease of cattle, buffalo, sheep, and pigs. The disease rarely affects humans, but the speed in which it spreads through livestock can seriously reduce milk and meat production, and the trade bans that result after outbreaks seriously affect the economies of food-exporting nations.

Researchers are excited about a novel livestock vaccine for foot-and-mouth disease developed by researcher Martin Grubman at the Plum Island Animal Research Center in New York in collaboration with the US Department of Homeland Security and GenVec, a biopharmaceutical company in Maryland. Luis Rodriguez, research leader at the Plum Island Animal Research Center, said studies of the vaccine candidate showed it was able to prevent clinical disease in cattle when they were challenged with the virus that causes foot-and-mouth disease.

Researchers are pursuing multiple paths to determine if antibodies can block HIV infection

Antibodies are Y-shaped proteins that work primarily by latching onto viruses and preventing them from infecting target cells. Antibodies are induced by most, if not all, existing vaccines and are thought to play a crucial role in the protection these vaccines afford.

While it is still unclear precisely what types of immune responses will need to be triggered by a vaccine to protect against HIV infection, many scientists believe that an AIDS vaccine will need to induce antibodies (see VAX February 2007 Primer on Understanding Neutralizing Antibodies). And because HIV is an incredibly diverse virus, with multiple clades or serotypes in circulation around the world, researchers are focusing on developing vaccine candidates that can induce antibodies that are capable of blocking or neutralizing many circulating HIV strains, so-called broadly neutralizing antibodies (bNAbs).

Such bNAbs against HIV exist. The immune systems of individuals who are naturally infected with HIV generate antibodies against the virus, some of which are broadly neutralizing. By screening blood samples from HIV-infected individuals, researchers have been able to isolate several bNAbs. Just recently, eight new bNAbs were discovered, some of which are more potent than those previously identified (see VAX March 2010 Primer on Understanding Advances in the Search for Antibodies Against HIV).

Researchers are now studying these bNAbs and using them to design vaccine candidates that would ideally be able to induce these antibodies in people before they are exposed to HIV, thereby protecting them against infection. However, this is a difficult task and it may take some time before vaccine candidates based on these bNAbs are ready for clinical testing. Until then, researchers are also conducting other studies in animals and humans to try to determine whether these bNAbs will be capable of blocking HIV infection.

Protection in animals

There is evidence from studies in animals to suggest that if scientists could learn how to induce bNAbs against HIV through a vaccine, they might be able to block infection. To evaluate this, researchers conduct what are referred to as passive immunization studies. In these studies, researchers inject bNAbs directly into animals and then purposely expose them to either HIV, or a hybrid virus known as SHIV that is a combination of HIV and simian immunodeficiency virus, the monkey form of HIV.

In studies with one of the bNAbs known as b12, scientists found that this antibody was able to block HIV infection in mice that were genetically altered to have human immune cells. In some studies, non-human primates passively immunized with b12 were completely protected against infection when they were purposely exposed to SHIV. While in other studies, infection of b12-immunized monkeys was delayed compared to those that were not immunized with b12.

Researchers are now planning to do similar studies in non-human primates with some of the newly discovered, more potent bNAbs to see how well they can protect against infection in animal models.

Evidence for protection in humans

Although these passive immunization studies in mice and non-human primates provide some evidence that bNAbs can block HIV infection from occurring, there is little evidence that this is also true in humans.

For many years, researchers have been studying individuals who although repeatedly exposed to HIV, seem to be able to ward off infection. Although it has been suggested that antibodies may be what protects these individuals from infection, in these cases, it is difficult to draw firm conclusions.

Another way researchers are attempting to learn if bNAbs can protect against HIV is by studying the passive transfer of maternal antibodies. Pregnant women pass antibodies to their fetuses through the placenta. If the mother is HIV infected, she may also pass HIV-specific antibodies to her fetus.

In a study of 100 infants born to HIV-infected mothers, researchers found that although the mothers had indeed transferred HIV-specific neutralizing antibodies to the infants, there was no evidence that these antibodies actually protected the infants against HIV infection during the breast-feeding period. While this suggests that these antibodies were not effective at blocking HIV, it does not mean that some of the newer, more potent bNAbs would not be effective.

To determine this, researchers are considering conducting a clinical trial of passive immunization in HIV-uninfected people. This type of study would show whether directly administering one or more of the more potent, recently discovered bNAbs into HIV-uninfected individuals through injection would protect them against HIV if they were naturally exposed to the virus.

Scientists are also hoping to conduct a clinical trial soon to evaluate another antibody strategy, known as gene transfer, to see if it can protect against HIV infection (see VAX November 2008 Primer on Understanding Approaches to Inducing Neutralizing Antibodies). Rather than directly injecting bNAbs, the gene transfer approach involves introducing the genes that could make the bNAbs into HIV-uninfected people.