Extending vaccine benefits to developing world will require innovation

VANCOUVER, British Columbia — Creative vaccine distribution strategies, improved vaccine technologies and more rapid manufacturing timetables were among ideas speakers at the 2010 Pediatric Academic Societies proposed during a symposium on vaccine-preventable diseases in the developing world.

Kathleen M. Neuzil, MD, MPH, professor of medicine at the University of Washington, senior advisor for immunizations at PATH, both in Seattle, and Advisory Committee on Immunization Practices member said that the lessons learned during this past season’s influenza A (H1N1) pandemic can be applied to distributing vaccines to people in low-resource settings.

“The virus was detected and characterized in record time, manufacturing capacity was at all time high and there were rapid organization and distribution efforts,” Neuzil said. “But we didn’t have enough vaccine, we didn’t get it out soon enough and distribution was not equitable.”

She noted that although H1N1 peaked during the third week of October in 2009, many physicians offices did not get the vaccine until much later, and many developing countries are just now getting their first allotment of H1N1 vaccine.

As director of PATH’s Influenza Vaccine Project, Neuzil and colleagues are exploring live-attenuated, recombinant and adjuvant vaccine approaches, as well as more broadly reactive antigens that offer more cross-protection, with longer-lasting immunity than the typical one or two years.

“Most of these are still in very early development,” Neuzil said.

Although the United States and Canada now have universal influenza vaccine recommendations, Neuzil acknowledged that this is a difficult goal to achieve, and highly unpractical for many countries.

Taking a high risk approach may be a more logistically sound strategy. Data from a randomized controlled trial that involved 340 pregnant Bangladesh women who received influenza vaccine, revealed that babies whose mothers received vaccine experienced a 28% reduction in illness compared with the control group.

Furthermore, influenza specific antibodies were higher among vaccinated mothers and infants, and infant geometric mean titers sampled at birth from cord blood were comparable to levels measured in the mother’s serum, according to Neuzil.

The PATH Initiative, in cooperation with the CDC, is currently evaluating the feasibility of vaccinating all 6-week to 10-week-old children in a village in Senegal to determine if this strategy will prevent influenza in the broader community. Last year, teams vaccinated about 86% of the village, and 98% of those who were supposed to receive a second vaccine did.

Despite these successes, Neuzil noted that researchers have a lot to learn. “Improving this technology so that it is no longer a yearly vaccination program will make a much more realistic strategy in many of these countries.”

Rotavirus challenges

Similar to the influenza vaccine, rotavirus vaccines are widely successful in the United States, but pose problems in developing countries, Roger Glass, MD, PhD, of the National Institutes of Health and the CDC viral gastroenteritis unit at the CDC, told audiences here.

Despite the fact that these vaccines have greatly reduced U.S. hospitalizations attributable to diarrheal illness with efficacy rates ranging from 85% to more than 90%, vaccine performance remains suboptimal in low-income countries.

Early findings from oral rotavirus vaccine use in developing countries show that immune responses correlate directly with the level of development of the country in which the vaccine is administered. Therefore, children in poorer countries were less likely to have good immune responses, Glass explained, similar to previous experiences with oral poliovirus vaccine.

The first studies of the live-attenuated oral monovalent rotavirus vaccine (Rotarix, GlaxoSmithKline) in South Africa indicated that only 36% of children aged 6 to 10 weeks developed an immune response. Similarly, M. Patel et al determined that in Nicaragua, 76% of 200 infants who were admitted to the hospital with rotavirus diarrhea had been vaccinated against the disease with the pentavalent rotavirus vaccine (RV5, Rotateq, Merck) compared with 83% in the control group, putting the efficacy of this other vaccine efficacy at only 46%.

Furthermore, additional studies with RV5 completed in five different developing countries — Bangladesh, China, Kenya, Mali and Vietnam — demonstrated that vaccine efficacy ranges from 1% to 72%, much lower than rates in countries such as the United States and Europe.

Researchers believe that interference from maternal antibodies may be partially to blame, according to Glass. Data from a study involving vaccine recipients in Finland indicated that those who failed to respond had significantly higher maternal antibody titers at the time of vaccination, suggesting that this transplacental antibody may impede a child’s immune response to the vaccine.

Glass said that many other factors may also interfere with immune responses, but that these remain poorly understood. In the meantime, several solutions have been proposed to overcome these issues, including delaying vaccination, increasing the potency of vaccine doses and withholding breastfeeding for a specified amount of time.

Additionally, two rotavirus strains that may be able to grow in the presence of maternal antibody are currently in development for a neonatal version of the vaccine — 116E in India and RV3 in Australia.

An inactivated, parenteral form of rotavirus vaccine is also under consideration. “Inactivated rotavirus vaccine is one way of having more uniform efficacy between children in developed and undeveloped countries. Inactivated vaccines are safer from intussusception, would not have same age restrictions, would cost less to develop and could be combined with other vaccines, making them easier to delivery,” Glass said. He noted that need for a research agenda to determine why oral rotavirus vaccines are less effective in developing countries was an “urgent.”

“We’ve clearly come a long way with rotavirus vaccines, but we still have a long way to go to stop death of 600,000 children per year,” Glass said. – by Nicole Blazek

For more information:

• Neuzil K, Glass R. #3455. Presented at: 2010 Pediatric Academic Societies Annual Meeting; May 1-4, 2010; Vancouver, British Columbia.

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