The influenza vaccines currently used in the United States are safe and effective at preventing flu and its complications. Yet, because they rely on flu virus grown in chicken eggs, the production process requires a large supply of fertile chickens and eggs and is entirely dependent on how well the virus grows in the eggs, making it very difficult to accelerate vaccine production in a time of influenza pandemic. This became apparent during the 2009 H1N1 influenza pandemic when accelerated vaccine production was needed, but the virus was slow to grow in eggs. The H1N1 outbreak underscored the need for new technologies to create and quickly deliver safe and protective flu vaccines to meet public health need.
Through the support of the U.S. Department of Health and Human Services and NIAID, researchers are developing new influenza vaccine technologies that will help the United States and the world be better prepared to mount a speedy response to the next pandemic.
Among the new influenza vaccine platforms that NIAID is exploring for potentially more efficient manufacturing and improved protection:
Innovative DNA-based influenza vaccines that do not require replication of the whole influenza virus are being developed and tested. These vaccines contain only portions of the influenza virus’ genetic material, which then “instruct” human cells to make proteins that elicit an immune response to flu virus.
To create a DNA-based vaccine, the gene of a particular protein is placed in a circular strand of DNA called a plasmid and injected directly into the host, or the arm of an individual. The gene begins coding for the protein and presents a gene of the influenza virus on the cell surface, similar to the way humans respond to antigens. By presenting the gene to the immune system in association with cellular elements, the immune system is triggered to respond. DNA-based vaccines are in various stages of development and testing for different diseases, including influenza.
Subunit vaccines typically include only the antigens that best stimulate the immune system, rather than all of the molecules that make up a microbe or virus. These types of vaccines can contain anywhere from 1 to 20 or more antigens. However, identifying which antigens best stimulate the immune system is a difficult and time-consuming process. Once researchers identify the antigens, they can manufacture the antigen molecules using recombinant DNA technology. These types of vaccines are called recombinant subunit vaccines, and have been successfully used to protect against hepatitis B.
Recombinant subunit flu vaccines make use of the hemagglutinin gene, which binds the virus to the cell being infected. The genetic material is placed into a vector, or carrier, virus that is harmless to humans; viruses that infect insect cells are often used. Once the vector delivers the hemagglutinin gene, protein harvesting and purification occurs within the cell culture. The individual viral proteins produced in cells are purified to a level not possible with vaccines started from a whole virus. Ultimately, the protein (rather than the whole virus) is injected into an individual, which then induces a potent immune response.
This vaccine approach involves inserting influenza virus genes into a different carrier virus, or vector, that is used as a vaccine. DNA or RNA-encoding influenza proteins, such as hemagglutinin, are engineered into a vector that infects humans but does not cause disease. With a microbial vector vaccine, the vector itself, including the influenza genetic material, is injected directly into a person. The harmless vector virus can then express the proteins necessary to prompt an immune response.
Synthetic peptide vaccines involve producing the influenza virus chemically, without growth in eggs or cell culture. Portions of influenza proteins that stimulate antibody production are synthesized and formulated into a vaccine to stimulate an immune response. Peptides alone stimulate a very weak immune response, but the use of an adjuvant or another method of delivering the peptide to the immune cells can strengthen that response.
A universal influenza vaccine would theoretically provide protection against all strains of influenza, without needing to be updated or administered every year to protect against newly emerging seasonal or pandemic flu strains. The targets for a universal flu vaccine include recently characterized portions of the hemagglutinin protein, which are conserved among all influenza subtypes; the M2 protein, located in the viral envelope; and the NP protein, which forms a scaffold required for virus replication. In 2010, NIAID’s Vaccine Research Center created and tested a universal flu vaccine that produced infection-fighting antibodies in mice, ferrets, and monkeys. In particular, the vaccine stimulated an immune response to the stem of hemagglutinin, which tends to remain constant from one influenza strain to another. In theory, antibodies generated against the hemagglutinin stem should be able to recognize and neutralize multiple flu strains. The researchers hope to begin large-scale human trials within the next five years.
A major focus of NIAID research is the development of new influenza vaccines. The testing of these experimental vaccines happens primarily in the Vaccine and Treatment Evaluation Units (VTEUs). Some other areas of focus include:
Looking at small areas in the influenza hemagglutinin gene, researchers are using different approaches to identify the best antigenic combinations. This involves looking for common epitopes, or parts of antigens to which antibodies attach, within the gene and placing them separately or in combination with certain proteins. Working with a particular DNA segment, researchers can insert other genes or receptors that will target the antigens to certain tissues and possibly elicit broader immune responses.
Optimizing delivery methods is also a focus for all of the new vaccine platforms NIAID is exploring. Areas of research include a “gene gun,” which would deliver vaccine directly into a person’s arm, and “bacterial ghosts,” which are bacterial membranes into which DNA could be inserted. As instructed by the bacterial proteins, the DNA would then travel to the individual’s lymphoid tissue and be ingested by the cells located there, stimulating an immune response.
Another NIAID research priority is improving the manufacturing and testing process for new flu vaccine platforms. Key questions include how to get a particular DNA segment to grow as rapidly as possible, how to maintain its effectiveness after it enters the cell, and how to encourage cells to rapidly manufacture a specific DNA sequence.
Last Updated January 14, 2011