Standard flu shots are currently designed to maximize serum antibody responses against prevalent viral strains. In so doing, they prevent viral pneumonia. The effectiveness of vaccines in preventing influenza infection of the nose and trachea, however, is extremely variable. Robert Waldman and I found, for instance, that the flu vaccine used one year was 95% effective but that the vaccine used in another year was only 27% effective. This was true even though the vaccines used in both years were good antigenic matches for that year's virus. This may be because flu vaccines do not uniformly stimulate secretory IgA.
More effective vaccines may come from current efforts to insert influenza virus genes into an appropriate vector. Vaccinia virus is one possible vector. In experiments performed with Smith and Moss at the NIAlD, we found that mice immunized intradermally with vaccinia virus containing the influenza hemagglutinin gene produced strong serum antibody and cell-mediated immune responses but no secretory IgA response. The vaccine prevented influenza infection of the lungs but not of the nose. It did, however, promote rapid recovery from nasal infection, probably because of a strong T-cell response.
Vaccinia virus may not be the ideal vector for an influenza vaccine, but our experience with it suggests that use of vectored vaccines has promise. Now that we better understand the pathogenesis of influenza and host defense mechanisms against the virus, it should be possible to develop a vaccine capable of stimulating all of the components of the immune system needed to prevent the disease. Our research group is currently collaborating with Dr. Moss' group at the National Institutes of Health in the evaluation of a replication deficient vaccine vectored derived from modified vaccinia virus Ankara (MVA).
MVA was developed for use as a smallpox vaccine from repeated (over 570) passages in chicken embryo fibroblasts. Genetic analysis revealed that MVA had suffered six major deletions of its genome, resulting in the loss of 30,000 base pairs (15% of its genome) so that it became host-restricted and unable to grow in mammalian cell lines. The block in replication of MVA in human cells occurs at a step in virion assembly rather than at an early stage of infection as happens with some other poxvirus host-restricted mutants. We found that MVA is avirulent when given to newborn or SCID (B-cell and T-cell deficient) mice.
During the Smallpox Eradication Programme MVA was given to 120,000 people, many at high risk of complications from the standard vaccine, without significant side effects. Using cimetidine and cholecystokinin to protect against acid and bile, mice were immunized by the intragastric administration of MVA containing the influenza hemagglutinin and nucleoprotein genes from H1N1 influenza virus. Two doses of the vaccine consistently induced serum anti-H1 IgG antibody that completely protected the lungs from challenge with H1N1. One dose gave partial protection. Almost all of the mice given two i.g. doses also developed mucosal anti-H1 IgA antibody. Those mice with high anti-H1 IgA titers (approximately half) had completely protected noses. Intramuscular injection of the vaccine protected the lungs but not the noses from challenge. In separate experiments, we found that the vaccine enhanced recovery from a shifted (H3N2) influenza virus probably through the induction of nucleoprotein-specific cytotoxic T-lymphocyte activity. These results suggest that a replication-deficient, orally administered, enteric coated, vaccinia-vectored vaccine could safely protect against influenza and perhaps many other diseases.
Biotechnology now makes it possible to create previously undreamed-of vaccines. Theoretically, it should be possible to insert genes from at least 10 to 15 pathogens into a single vector and with one capsule or injection to prevent 10 to 15 diseases. Currently, the major impediment to development of such vaccines seems to be a lack of adequate funding. The Children's Defense Fund has estimated that every dollar spent on vaccine production and use saves ten dollars in health care costs. Funds spent on vaccine research and development may be an even better investment.
In the interim, until a better vaccine is available, it is important that the elderly (beginning at age 65) and other high-risk groups receive annual flu shots. Included are patients with increased pulmonary capillary pressure and chronic heart, lung, or other diseases and children or teenagers receiving continuous aspirin therapy. Flu shots will not necessarily prevent influenza infection, but they should prevent viral pneumonia. Also important is prophylactic use of amantadine in high-risk unvaccinated patients and in newly immunized high-risk patients when an epidemic is under way: a three-week course will provide coverage for the period between immunization and development of protective antibody. Appropriate management of high-risk groups can save thousands of lives annually.
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