The current strains of influenza A(H1N1), A(H3N2), and B are grown separately in the allantois of chick embryos, inactivated with an appropriate chemical such as p-propiolactone, then purified by zonal ultracentrifugation, disrupted with detergent, and pooled. The resulting polyvalent inactivated vaccine is inoculated each autumn. Although some countries direct their program at schoolchildren with a view to limiting the circulation of virus in the community, thereby protecting the whole population, most do not regard this as a realistic proposition. It is generally not considered cost-effective or necessary to immunize the whole community, but only the most vulnerable cohorts, namely, (1) the elderly (>65 years), (2) residents of nursing homes and other chronic care facilities, (3) those (of any age) with chronic debilitating disease of the pulmonary, cardiovascular, renal, or endocrine systems (asthma, emphysema, chronic bronchitis, cystic fibrosis, diabetes, etc.), and (4) those with compromised immune function. In bad epidemic years there may also be a case for immunizing medical personnel and others providing vital community services, as well as close relatives and home-care personnel attending high-risk invalids.
The commonest side effect is a mild local reaction: some tenderness, redness, and swelling occur around the injection site in about 15% of recipients. Less frequently fever, malaise, and myalgia may develop within hours and disappear a day later. The only major contraindication for influenza vaccine use is known allergy to eggs; though the allergy is rare, inoculation of such persons can produce an immediate allergic reaction. A particularly serious problem, the Guillain-Barre syndrome, was encountered in 1 in every 100,000 Americans vaccinated against influenza A/New Jersey/76 (H1N1), during a mass campaign in 1976-77 to protect the population against an outbreak of "swine flu" which did not spread widely anyway, but no such association has been reported with any previous or subsequent influenza vaccine (see Chapter 9).
Efficacy is highest in the young and lowest in the old. There are probably two reasons for this difference. First, immune responsiveness declines with age; second, "original antigenic sin" tends to divert the response to influenza vaccines in the elderly, which is a great pity because that cohort constitutes the principal target group of annual vaccination campaigns. However, even though antibody rises following vaccination in the elderly are often disappointing and there is generally only a 30-70% reduction in the incidence of influenza, there is a 60-90% reduction in pneumonia, hospitalization, and mortality, providing that there is a good match between the vaccine strain and the challenge strain of virus. In so far as severe illness and death are what we are really aiming to prevent by immunization of the elderly, it can be asserted that current influenza vaccines, while less than perfect, offer a worthwhile degree of protection.
There has been much debate about whether the vaccine virus should continue to be grown in embryonated hen's eggs rather than in cultured mammalian cells such as MDCK, in light of the observation that replication in chick embryos tends to select for variants with preferential affinity for the avian cell receptor; the favored mutations affecting the HA ligand sometimes also alter the antigenic characteristics of the virus. The current view is that the greater convenience of and experience with the chick embryo argue for its continuation, provided that the vaccine seed stock is a clone demonstrated to j be antigenically identical to the original human isolate.
Research is progressing on a number of fronts to find a better approach to vaccination against influenza. Some approaches are directed simply at increasing the immunogenicity of inactivated virions, or of solubilized or genetically cloned HA (± NA), lor example, by addition of adjuvants, coupling to carriers, or incorporation into liposomes, virosomes, or iscoms (see Chapter 13). However, none of these approaches addresses the most critical problems of all, namely, (1) antigenic shift and drift and (2) the inability of inactivated vaccines to generate either a local IgA or a cell-mediated immune response. A topically administered live vaccine producing a mucosal IgA, IgG, and T-cell memory response of broad cross-reactivity within a type or subtype may be the answer.
Cold-adapted (ca) variants of influenza virus with mutations in every gene have been developed and used as master stains for genetic reassortment (see Chapter 4) with contemporary strains of influenza to produce an attenuated vaccine virus containing 6 ca genes plus wild-type HA and NA genes (see Chapter 13). When the ca vaccine is administered by aerosol spray or intra-nasally, the replication of virions is restricted to the nasopharynx. During a long history of successful use in Russian schoolchildren and clinical trials in United States, these ca vaccines have been demonstrated to be stably attenuated for humans, with no reversion to virulence and no evidence of secondary transmission. They display good immunogenicity and efficacy in influenza-naive infants, but replicate poorly and are much less effective in adults, and are of no value in the elderly. A case can be made for their use in high-risk infants, provided evident problems of interference can be overcome by careful balancing of. the titers of the A/HI, A/H3, and B strains in trivalent live vaccines.
Attention is also turning to the possibility of oral delivery of influenza vaccine, taking advantage of the common mucosal system. Inactivated or live virions have been mixed with potent adjuvants such as the heat-labile Escherichia coli toxin (LT), or enclosed in biodegradable microspheres, and shown by oral administration to mice to elicit a protective (and sometimes cross-reactive) secretory IgA antibody response in the lungs.
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