Attacking Global Diseases in the 21st Century
NFID conference showcases how vaccines are gaining ground against global scourges.
Edward Jenner’s experimental smallpox vaccination of a small boy in 1794 may have been deeply unethical, but it certainly changed the world. The country doctor famously used cowpox pus to immunize the boy—and then scratched him with pus collected from a smallpox victim to test a hunch about immunization. The experiment worked, igniting a chain of events that not only culminated in the eradication of smallpox in 1980 but also spawned a biomedical revolution that has dramatically reduced the incidence of many other dreaded diseases over large swathes of the world.
As Stanley Plotkin, a leading authority on vaccines, has pointed out, the only thing that has saved more lives and done more for public health than vaccination is access to clean water. But in his May 7 keynote address that kicked off the Fifteenth Annual Conference on Vaccine Research in Baltimore, Plotkin—who invented the rubella vaccine now used worldwide—noted that the low hanging fruit have all been plucked. The design of vaccines against the remaining preventable diseases has become a far more complex affair, and their subsequent development much more expensive. Future vaccines, he noted, will likely be biochemically complex, include novel adjuvants and be used selectively—on the basis of genotype—in populations in which they’re likely to work.
Future AIDS vaccines are no exception. The first generation of such vaccines, Plotkin guessed, will be delivered in a prime-boost regimen and consist of a clade-specific gp120 protein from the HIV envelope or, perhaps, multiple gp120s that induce neutralizing and non-neutralizing antibodies targeting the V1-V2 and V3 regions of that protein. They will probably also be formulated with a strong adjuvant. Further, people will in all likelihood require periodic booster shots of such vaccines to sustain immunity.
Not quite Jenner’s vaccine.
Plotkin’s talk set the tone for three days of discussion on the new world-order of vaccine research, beginning with a whole series of talks on progress toward reducing the incidence of rotavirus—the most common cause of diarrheal disease in developing countries. Malaria, which might well join the ranks of vaccine-preventable diseases by 2015, got its share of attention as well, as did influenza, which faces a crowded pipeline of preventive vaccine candidates. Other sessions highlighted next-generation adjuvants, an area of growing interest to many vaccine researchers.
Crowning the three days of talks at the conference, which was sponsored by the National Foundation for Infectious Diseases in Maryland, was one that showcased what can happen when all the pieces of the vaccine design and delivery puzzle are brought together effectively. Marc LaForce, who retired as director of the Meningitis Vaccine Project (MVP) in March, described the highly successful campaign that was launched at the end of 2010 to begin eliminating serogroup A Neisseria meningitidis from Africa’s meningitis belt. The region stretches from the Gambia in West Africa across to central Ethiopia, and it accounts for roughly 90% of the global burden of meningococcal disease. About 85% of all meningococcal meningitis cases are caused by serogroup A of the bacterium, which is spread through the exchange of saliva and other respiratory secretions. The disease is unpredictable. It can be relatively mild, resulting in stiff neck, fever and rash. But severe cases can cause meningitis, result in lifelong mental and physical disability or move rapidly to systemic infection, coma and death.
“Making vaccines is not for cowards,” remarked LaForce, who had just accepted the Albert B. Sabin Gold Medal Award from the Sabin Vaccine Institute the night before, as he described efforts begun more than a decade ago to develop an inexpensive vaccine against group A following an epidemic in 1996 that infected 188,000 individuals. In 2001, the World Health Organization (WHO) and the non-profit global health organization PATH formed MVP with support from the Bill & Melinda Gates Foundation. Its goal was to develop an affordable conjugate vaccine that would provide immunity lasting much longer than the 2-3 years afforded by existing polysaccharide vaccines against groups A, C, W135 and Y, which have been around for 30 years.
To make mass vaccination against meningitis affordable in Africa, said LaForce, the vaccine had to cost less than 50 cents a dose. Further, surveillance systems had to be upgraded. Large vaccine developers were reluctant to become involved in developing a meningitis vaccine exclusively for the cash-strapped developing world, he said, but the MVP eventually found a partner in the India-based Serum Institute.
MenAfriVac, which coupled an older meningitis vaccine with a tetanus protein to boost immune responses, was rolled out in Burkina Faso, Niger and Mali in late 2010. Immunizations continued last year in Cameroon, Chad and Nigeria. The mass vaccination campaign, which spans 22 countries, is scheduled to be completed by 2016. Early epidemiological surveillance in three districts in Burkino Faso—where the first injections were given—found evidence of herd immunity, said LaForce. More than 20,000 throat cultures obtained in Burkina Faso pre- and post-vaccination found no evidence of the group A bacterium after MenAfriVac was administered, strong evidence that it had stopped circulating, he said.
And while 11,647 cases of meningitis were reported between January and April this year in 10 countries, including those where the MenAfriVac vaccine has been administered, the outbreaks were mainly caused by the W135 serogroup of N. meningitidis, which is not covered by the vaccine.
LaForce said the first phase of MVP, aimed at eliminating group A meningococcus, seems to have worked. “But once you get rid of a large fraction of the problem, what is left behind becomes intolerable,” said LaForce. “So the next phase will be to develop a polyvalent meningitis conjugate vaccine that is also affordable.” LaForce has joined the Serum Institute part time as director of technical services to do just that.
Taking aim at rotavirus
The MenAfriVac campaign provides a template for mass vaccination in resource-constrained regions with poor health infrastructure. Other equally ambitious immunization campaigns are underway today as well. A rotavirus vaccination campaign steered by the GAVI Alliance, a Geneva-based global health partnership launched in 2000 to increase immunizations, is one of them. The NFID conference highlighted some of the challenges faced by that effort. The rotavirus vaccine is available in industrialized countries but is only now being rolled out in impoverished countries like Sudan, which last September became the first African country to begin offering that vaccine.
An older rotavirus vaccine known as Rotashield was removed from the market in 1999, after it was associated with an increased risk of intussusception—a rare type of bowel obstruction that occurs when the bowel folds in on itself. Without proper treatment, intussusception can lead to necrosis of the bowel and perforation, which can be fatal. No such risk was found in large clinical trials of GlaxoSmithKline’s (GSK’s) Rotarix and Merck’s RotaTeq—live attenuated vaccines that are orally administered—but post-licensure safety investigations have since identified a very low risk of intussusception associated with the Rotarix vaccine in Mexico and Australia, and with the RotaTeq vaccine in Australia.
Post-licensure studies in the US uncovered no such cases, however. Umesh Parashar, a team leader for the viral gastroenteritis team at the US Centers for Disease Control and Prevention (CDC), said the low-level of risk of intussusception—about 1-2 cases per 100,000 vaccinations—has to be considered against the benefits of rotavirus vaccination and risks of rotavirus-related disease. “In Mexico,” he observed, “nationwide use of Rotarix vaccine would prevent approximately 12,000 hospitalizations and 700 deaths from diarrhea each year, a benefit that outweighs the risk of vaccine-associated intussusception of about 40-50 cases.”
Yet studies have also found the efficacy of RotaTeq and Rotarix vaccines can vary dramatically between infants in industrialized countries and those in the developing world. In industrialized countries, the vaccines were found to be between 85% and 100% effective in preventing severe gastroenteritis among infants in upper and middle-income countries during the first year of life. But in poorer countries, the efficacy was significantly lower. One study in Malawi, for instance, found Rotarix only 49% effective in preventing severe gastroenteritis among infants during the first year of life, and it was as low as 18% in the second year of follow-up. Similarly, an efficacy trial of RotaTeq conducted in Ghana, Mali and Kenya found vaccine efficacy to be 64% during the first years of life and only 51% in Bangladesh and Vietnam.
Kathleen Neuzil, a University of Washington global health scientist connected with PATH, which is providing technical support to countries in Africa and Asia for rotavirus vaccine introduction, told conference attendees that co-administration of the oral polio vaccine could be interfering with the immune responses of the rotavirus vaccine in infants. One study suggests that the impact of the OPV is likely to be greatest following the first dose of RotaTeq at six weeks of age, compared to the second and third RotaTeq doses at 10 and 14 weeks of age (1). Circulating maternal antibodies, which are known to interfere with vaccine uptake, remain at high levels six weeks after delivery.
Other factors that could be contributing to the lower efficacy of rotavirus vaccines in developing countries are malnutrition and an unhealthy gut environment. Researchers have found that immune responses to oral vaccines are lower among children in developing countries, and they think that malnutrition is probably exacerbating immune system dysfunction—and vice versa—with unfortunate results. At a conference last year devoted to gut health and vaccine efficacy, Gagandeep Kang, professor and head of the Wellcome Trust Research Laboratory at the Christian Medical College in India said malnutrition seems to cause the gut to fail to serve as a barrier to pathogens. Infection then further damages the gut and affects the absorption of nutrients, which in turn makes the malnutrition worse. (see A Gut Response to Vaccines, IAVI Report, Nov.-Dec. 2011).
Neuzil said more studies are needed to sort out these data and to determine ways of improving vaccine responses. But despite the lower efficacy, Neuzil echoed Parashar’s point that even moderately effective rotavirus vaccines have the potential of doing much good in developing countries.
The hunt for a safe, effective AIDS vaccine continues to pose serious challenges, but progress in both the development of more potent DNA vaccines—a field that has languished in recent years—and next generation adjuvants are cause for optimism.
David Weiner, chair of the gene therapy and vaccines program at the University of Pennsylvania, talked about how improvements in the design of DNA platforms, aided by electroporation and adjuvants, are producing more potent immune responses without a boost, thus expanding research options. Weiner’s lab, for instance, has been improving on DNA plasmids—DNA circles that are taken up by immune cells through vaccination in hopes of eliciting an immune response. His team has designed plasmids that encode consensus gene sequences from clades A and C in the hope of producing the most broadly effective immunogens possible. The DNA vaccines are delivered via electroporation to improve the uptake of DNA into cells, which helps improve immune responses. The DNA plasmids also include adjuvants, such as IL-12 or CCR10, which is commonly expressed on IgA-secreting cells that direct the immune responses to mucosal regions.
Recent findings from animal and clinical studies have been encouraging, said Weiner. His lab has been collaborating with the company Inovio Pharmaceuticals to test three DNA vaccine candidates for AIDS. Their recently concluded Phase 1 trial involving 48 adults in the US found T cell responses from one of those candidates—PENNVAX-B targeting HIV Gag, Pol and Env proteins from a clade B strain—were highest among a menu of HIV vaccine candidates, including those employing adenovirus and modified vaccinia Ankara viral vectors. In the PENNVAX-B study, three doses of the vaccine were delivered along with an IL-12 plasmid adjuvant using electroporation. The study found that 89% of the vaccinated recipients mounted T cell responses against at least one of the antigens. Weiner said the same PENNVAX-B regimen in nonhuman primates, but with a different electroporation configuration, was able to elicit antibody responses that neutralized sensitive Tier 1 viruses.
A boost to RV144
Robert Seder, chief of the cellular immunology section at the Vaccine Research Center of the US National Institute of Allergy and Infectious Diseases gave a separate talk on adjuvants. His focused specifically on the RV144 trial in Thailand, which found modest 31.2% efficacy with the ALVAC-HIV (vCP1521)/AIDSVAX B/E prime-boost regimen. While the trial was historic—providing the first evidence of vaccine-induced protection against HIV—the waning effect of the vaccine over time has raised questions about whether additional boosting would have proved more effective and, if so, which adjuvants might have worked best with the DNA-based vaccine.
Alum—the most commonly used adjuvant—was used in the AIDSVAX boost, but data presented by Seder suggests that other adjuvants may produce better responses. Ongoing studies in a cohort of 54 nonhuman primates have been ranking the performance of adjuvants in improving cellular and humoral immune responses to HIV Env (see A Vaccine’s Little Helper, IAVI Report, May-June 2011). Along with alum, the list includes lesser-known products like poly-ICLC, a synthetic double-stranded RNA that binds to a toll-like receptor (TLR). The animals were immunized four times over a two-year period.
Perhaps the most telling finding from the measurement of humoral immune responses was that the animals that were given an adjuvant other than alum maintained stable titers over 80 weeks, while the titers in the HIV Env-only arm or HIV Env and alum arm went up and down between the boosts. “You get remarkably higher [antibody] binding titer than alum alone,” said Seder. —Regina McEnery
1. Vaccine 30, Sup 1 A30, 2012