PATH has begun new work to investigate possible vaccine development strategies against respiratory syncytial virus (RSV), one of the world’s most important causes of acute lower respiratory infection (ALRI) in young children. With initial funds reprogrammed from a Bill & Melinda Gates Foundation-supported project in PATH’s vaccine development program, PATH is analyzing the RSV vaccine development landscape and has issued a request for letters of intent to identify vaccine products in early-stage development that might be appropriate for disease prevention in resource-constrained countries. According to a recent review, RSV is responsible for over 30 million new ALRI episodes worldwide and up to 199,000 deaths in children under five years of age. In the United States alone, the virus infects nearly all children at least once by the age of two and is the most common cause of bronchiolitis and infant pneumonia, resulting in up to 125,000 hospitalizations each year. Although RSV is less understood in the developing world, available data suggest that a significant proportion of ALRI among children in low-resource countries is due to RSV, particularly in the first months of life. The pervasive disease also leads to substantial economic hardship in low-income countries where hard-to-reach healthcare, hospital costs, and lost livelihoods make caring for the sick particularly burdensome for caregivers, households, and communities.

Despite these impacts, no RSV vaccine exists today because an incomplete understanding of the body’s immune response to the virus has challenged and delayed RSV vaccine development efforts. Palivizumab, the only drug specifically indicated for preventing RSV disease severity in high-risk infants, cannot treat or cure already-serious RSV infection. Availability, cost, and treatment logistics make its use impractical in resource-constrained settings. PATH’s new explorations into potentially promising RSV vaccine technologies is an important step toward addressing the global need for a way of controlling this wide-reaching disease through prevention.

Studies have shown that administering certain vaccines to pregnant women can help improve the mother-to-child transmission of antibodies, which can provide critical short-term protection during the early stage of a newborn’s life when direct vaccination is not an effective option. In contribution to the scientific dialogue on maternal immunization as an effective way of protecting mothers and infants from infectious diseases, Drs. Kathleen Neuzil and Justin Ortiz of PATH’s influenza vaccine project recently co-authored a paper published in Vaccine entitled Influenza vaccine for pregnant women in resource-constrained countries: A review of the evidence to inform policy decisions. The article provides an overview of the available research supporting maternal immunization with influenza vaccine as a cost-effective way of reducing influenza morbidity among pregnant women and infants in the developing world, two groups hardest hit by the virus. Dr. Neuzil also recently participated in a maternal immunization satellite session at the World Health Organization’s Initiative for Vaccine Research Global Vaccine Research Forum in Geneva, Switzerland, on June 26, 2011, where she presented on the global maternal immunization landscape for various disease targets and moderated a session on safety standards and key research questions for maternal immunization. In addition, she is scheduled to present at the 51^st Interscience Conference on Antimicrobial Agents and Chemotherapy on issues surrounding maternal and neonatal vaccination.

In other news, Dr. Ortiz recently co-authored a review published in Influenza and Other Respiratory Viruses entitled Pandemic influenza in Africa, lessons learned from 1968: A systematic review of the literature. The article reviews published data on pandemic influenza virus infection in Africa from January 1950 through August 2008, a time period covering the influenza A(H2N2) pandemic of 1957 and the influenza A(H3N2) pandemic of 1968.

The Government of India’s Department of Biotechnology (DBT), Bharat Biotech International, Ltd. (BBIL), and PATH’s rotavirus vaccine development project are working together to assess the efficacy of the 116E rotavirus vaccine candidate in a Phase 3 clinical trial that launched in March. The randomized, double-blind, placebo-controlled trial will last approximately three years, enrolling a total of 6,800 infants at three sites in India: the Centre for Health Research and Development at the Society for Applied Studies in New Delhi, Shirdi Sai Baba Rural Hospital at the King Edward Memorial Hospital Research Centre in Pune, and Christian Medical College in Vellore. To date, more than 3,500 infants have been enrolled in the trial. This study has been made possible through funding from DBT, the Bill & Melinda Gates Foundation, and BBIL, as well as targeted support from the Research Council of Norway’s Programme for Global Health and Vaccination Research, as a part of the Indo-Norwegian collaboration on vaccine research.

Since 2001, PATH has been part of a collaborative effort to develop and test the 116E rotavirus vaccine candidate. This collaboration emerged from the Vaccine Action Program—a cooperative effort of the Indian and US governments being implemented by DBT and the US National Institutes of Health—and drew on the seminal efforts of several leading experts in the rotavirus field, including Drs. M.K. Bhan, T.S. Rao, Roger Glass, Harry Greenberg, George Curlin, Durga Rao, and Nita Bhandari. The 116E vaccine contains an attenuated strain of rotavirus originally isolated from neonates in the nursery at the All India Institute of Medical Sciences in 1985. It is an oral vaccine administered to infants in a three-dose course at the ages of 6, 10, and 14 weeks.

PATH recently initiated new partnerships with several organizations for preclinical research of non-replicating rotavirus vaccines (NRRVs). Blue Sky Biotech (Worcester, MA, USA) will perform early-stage process development for a VP8 recombinant protein, synthesized and developed by DNA2.0 (Menlo Park, CA, USA). Covance Inc. (Princeton, NJ, USA) is conducting a preclinical study designed to evaluate the magnitude and breadth of the immune response engendered by four NRRV candidate vaccines. Finally, the Cincinnati Children’s Hospital Medical Center (Cincinnati, OH, USA) will determine the ability of immune serum to neutralize rotavirus strains expressing predominate serotypes among field isolates. The study is underway, and results expected in the coming weeks will allow PATH to identify the vaccine candidates appropriate for further clinical development.

PATH’s enteric vaccine project is supporting the August launch of a Phase 1 trial of a live attenuated Shigella vaccine candidate in Baltimore, Maryland. This oral vaccine, CVD 1208S, was developed by the Center for Vaccine Development (CVD) at the University of Maryland, and it is ultimately envisioned to be a multivalent vaccine designed to prevent illness resulting from common disease-causing strains of the Shigella bacteria. Researchers are administering up to three doses (instead of the single dose historically used in earlier Shigella vaccine trials) of CVD 1208S or placebo to the nearly 75 healthy adults participating in the study, which is testing up to four different dosage levels. The trial is expected to conclude by November 2012 with results available by March 2013.

As reported in previous issues of Vaccines for the Future, PATH supported an earlier Phase 2 trial of CVD 1208S, which was halted in February 2010 because a small number of study participants experienced unacceptable reactions to the study vaccine. By administering a series of three doses of vaccine in a carefully controlled dose-escalation study and using a new vaccine lot prepared under Good Manufacturing Practices, PATH and CVD expect that the Phase 1 trial design will optimize the chances of identifying a safe dosing regimen that induces strong immunity.

Staff from PATH’s pneumococcal vaccine project participated in a working group led by the US Food and Drug Administration (FDA) that recently completed the development of a new Streptococcus pneumoniae human reference serum, 007sp. This reference serum provides a standardized reference point for assays measuring immune responses to pneumococcal conjugate vaccines (PCVs) and replaces the nearly exhausted supply of its predecessor, Pneumococcal Human Reference Serum lot 89SF. To provide the evidence needed to support 007sp as the new reference standard, the working group organized and completed a multi-laboratory study that successfully bridged 007sp to 89SF. Now finalized and available for use, 007sp is being shipped by FDA to sites for testing existing and newly-developed PCVs through immune assays such as enzyme-linked immunosorbent assays (ELISA). Overall, the new reference serum is essential for speeding the development and deployment of lifesaving PCVs by enabling uniform, efficient, and continuous PCV testing.

In other news, Dr. Mark Alderson, director of the pneumococcal vaccine project at PATH, presented on the state of the development pipeline for pneumococcal protein vaccines at the World Health Organization’s Initiative for Vaccine Research Global Vaccine Research Forum in Geneva, Switzerland, on June 27, 2011. The session brought to light the potential of protein vaccines to provide broad, affordable protection across many, if not all, of the more than 90 serotypes of S. pneumoniae. As part of a comprehensive portfolio approach to preventing pneumococcal disease, PATH is working to accelerate the development of protein-based vaccine technologies, as well as new, more affordable PCVs, to meet the needs of children in low-resource countries.