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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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FDA-Led Study Describes Mechanism Potentially Responsible for Respiratory Side Effect Associated with a Pig Influenza Vaccine

 

The results of a study in pigs led by scientists at the U.S. Food and Drug Administration (FDA) suggest that researchers attempting to develop a “universal” influenza vaccine that targets a specific part of influenza viruses called the HA stem should consider the possibility that some antibodies triggered by such a vaccine might enhance influenza disease rather than prevent it. 

 
The current process of making, distributing and administering millions of doses of seasonal influenza vaccines could become obsolete if researchers could develop a universal influenza vaccine that provides long-term protection from any influenza virus strain that may circulate.

 
Although the vaccine used in the study is specifically for pigs and is not the same type of influenza vaccine that millions of people receive every year, the results of the study will help scientists in their efforts to develop safe and effective universal influenza vaccines for use in people. The FDA study describes a particular mechanism that may underlie triggering of the production of antibodies that may affect the safety of a particular type of universal vaccine.

 
Vaccines that prevent influenza trigger production of antibodies against a protein called hemagglutinin (HA). These antibodies inhibit virus infection by blocking HA from binding to cells in the body. HA is therefore the key component of most influenza vaccines. The HA protein of influenza viruses is composed of a globular head that the viruses use to initially attach themselves to cells and a second section called the stem region. One section of the stem region, called the fusion peptide, enables the attached viruses to fuse tightly to the cells and infect them.

 
The antibodies that would be triggered by a universal vaccine are called cross-reacting antibodies because they attack targets on other influenza viruses that are conserved, that is, the targets do not mutate readily and therefore are very similar or identical from one influenza virus to another. The goal of some universal vaccines in development is to elicit antibodies that exclusively target the stem region of the HA and block virus fusion, thereby slowing or blocking target cell entry. The traditional inactivated influenza vaccines licensed by FDA primarily elicit antibodies that bind to the globular head rather than the stem region, and block influenza virus matching the strains of influenza virus included in the vaccine from binding to its receptor on target cells.

 
In the study, the scientists investigated why some pigs that were administered an influenza vaccine for pigs and challenged with a mismatched live influenza virus developed enhanced pneumonia and respiratory disease when compared with unvaccinated pigs after infection with an influenza virus. 

 
Specifically, the scientists vaccinated the pigs with an inactivated vaccine for pigs (a killed virus that is unable to cause influenza disease) that was designed to protect against the influenza virus strain H1N2. They then exposed the vaccinated pigs to a “challenge” virus—a virus different from the influenza strain that the vaccine prevents—called pH1N1, the virus that caused the 2009 influenza pandemic.

 
Following infection by pH1N1, some of the pigs vaccinated against H1N2 developed severe pneumonia and lung damage. The scientists determined that the inactivated H1N2 vaccine triggered effective antibodies against H1N2 viruses, which targeted the globular head of HA and prevented H1N2 viruses from binding to cells in the pigs. However, the globular HA head on the pH1N1 used for the challenge was not sufficiently similar to that of H1N2 for the antibodies to recognize it. Therefore the antibodies triggered by the H1N2 vaccine were able to bind only poorly to the globular head of HA on pH1N1 viruses and were not able to prevent them from attaching to cells.

 
At the same time, the H1N2 vaccine did trigger strong cross-reactive non-protective binding antibodies against the stem region of HA on pH1N1 because that area was very similar on both H1N2 and pH1N1. But these antibodies bound to an area near the fusion peptide, and actually increased fusion activity of the pH1N1 virus to the membrane of the cell, which enhanced influenza disease after the vaccinated animals were exposed to the pH1N1 virus.

 
The results of this study contribute to the ongoing research efforts toward developing safe and effective universal influenza vaccines.  Public health officials have great interest in using such universal vaccines to reduce or eliminate the need to manufacture a new influenza vaccine every year. The eventual development of a universal vaccine could also reduce illness and the number of deaths caused by a fast-moving influenza epidemic caused by a new strain of the virus. In such cases a universal vaccine could be used until a vaccine specifically developed for the epidemic virus is approved by FDA and ready for distribution.
 
Title
“Vaccine-induced anti-HA2 antibodies promote virus fusion and enhance influenza virus respiratory disease”
Science Translational Medicine
5, 200ra114 (2013)

 
Authors
 Surender Khurana1, Crystal L. Loving2, Jody Manischewitz1, Lisa R. King1, Phillip
 C. Gauger3, Jamie Henningson4, Amy L. Vincent2*, and Hana Golding1*
 
 1Division of Viral Products, Center for Biologics Evaluation and Research (CBER),  FDA, Bethesda, MD, 20892
2Virus and Prion Research Unit, National Animal Disease
 Center, USDA, Agricultural Research Service, Ames, IA, 50010
3Department of Veterinary Diagnostic and Production Animal Medicine, Ames IA, 50010, USA
 
 4Kansas State Veterinary Diagnostic Laboratory, Manhattan, KS, 66506, USA