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Live-Attenuated Influenza Vaccine (LAIV)
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• Rationale for an intranasal influenza vaccine is predominantly ease of administration, increased use, broader immune response, induction of mucosal immunity, ability to rapidly update vaccine in event of antigenic changes, and possibility of cross-strain protection.
• Appearance of virulent strains of influenza A(H5N1) in Southeast Asia and the potential for pandemic spread underscore the need for vaccines with these advantages.
• Cold-adapted strains of influenza virus were developed by serial passage in chick embryo cells at successively lower temperatures. These temperature-sensitive mutants grow at 77°F (25°C), but their replication is restricted at 100.4–102.2°F (38–39°C).
• The strains have been used as the basis for LAIVs because they replicate in the cooler temperatures of the upper airway, inducing broad systemic and mucosal immune responses but few symptoms. However, they do not replicate in the warmer environment of the lower airways and are therefore incapable of causing pneumonia or other more serious influenza syndromes.
• To prepare vaccine for a given season, the parental cold-adapted strain is co-cultured with the prevailing epidemic strains; reassortants that contain 6 internal genes from the cold-adapted strain + the hemagglutinin and neuraminidase genes from the prevailing strains are selected. These reassortants have the temperature-sensitive and cold-adapted phenotype of the parental strain but induce immunity to the prevailing strains.
• Since 1976, monovalent, bivalent, and trivalent LAIVs have been evaluated in individuals of all ages. These studies have confirmed that the vaccines are genetically stable and well tolerated. Although the vaccine virus is shed in low titer for as long as 9 days, horizontal transmission is very unusual. Reversion to virulence or wild phenotype has not been observed.
• Demonstrable immune responses include serum antibodies, IgA in nasal secretions, T-cell responses, and interferon production. Cell-mediated responses against heterologous strains of influenza have been seen, something that does not occur with the inactivated vaccine.
• FluMist (LAIV) was developed by Aviron during the 1990s. In 2002, MedImmune acquired Aviron and partnered with Wyeth for global marketing of FluMist after licensure. Based on data from 20 clinical trials including 20,228 individuals who had received at least 1 dose of vaccine and 8,469 who had received placebo, licensure for use in healthy persons aged 5–49 yrs was granted on June 17, 2003.
» FluMist contains approximately 106.5–7.5 infective units of LAIV (50% tissue culture–infective doses, or TCID50) per 0.5-mL dose (the syringe-like spray applicator sprays half of this total dose into each nostril); the 3 influenza strains (2 influenza A and 1 influenza B) recommended each year by the FDA is included.
» The vaccine is grown in eggs, harvested, purified, and stabilized with buffer containing sucrose, potassium phosphate, and monosodium glutamate.
Storage, Handling, and Administration
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Inactivated Influenza Vaccine
• Maintain temperature at 35–46°F (2–8°C).
• Freezing can cause the vaccine to lose potency.
• Shake well before use.
• Each dose is 0.5 mL given IM
LAIV
• Keep frozen at 5°F (–15°C).
• Freezer must have a separate sealed freezer door.
• Dormitory-style refrigerators with internal freezer compartments should not be used.
• If a frost-free model is used, vaccine should be placed in the manufacturer-supplied freezer box (FluMist FreezeBox); this requirement does not apply to vaccine shipped between December 31, 2003 and March 31, 2004, which was approved for storage in conventional frost-free models without the insert.
• Vaccine may be thawed by holding in the palm of the hand immediately before administration (vaccine can also be thawed in the refrigerator [35–46°F (2–8°C)] but must be used within 24 hrs); do not refreeze after thawing.
• With the individual in the upright position approximately 0.25 mL (half the dose from a single syringe) is sprayed into the first nostril, after which the dose-divider clip is removed and the remaining vaccine is delivered into the second nostril.
• Do not readminister if the patient sneezes.
Schedule
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• Influenza vaccine is usually given in October and November of each year but should still be given throughout influenza season. To avoid missed opportunities, high-risk individuals can be vaccinated when seen for other reasons as early as September.
• No influenza vaccine should be used in infants aged <6 mos, and LAIV should only be used for healthy individuals aged 5–49 yrs. Between age 6–35 mos, the dose of inactivated vaccine is 0.25 mL, and at 36 mos, the dose is 0.5 mL.
• Children aged 8 yrs who are being vaccinated for the first time with inactivated vaccine should receive 2 doses separated by 1 mo (the second dose should be received before December); if LAIV is used, 2 doses are also indicated, but the separation between doses should be 6–10 wks. If the child ever received influenza vaccine in the past (regardless of which vaccine was used), only 1 dose is indicated—e.g., a child who received inactivated vaccine at 1 yr of age and is to receive LAIV at 7 yrs of age should receive only 1 dose.
Efficacy
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Inactivated Influenza Vaccine
• Nearly all vaccinated young adults develop hemagglutinin-inhibition antibody titers that are likely to be protective against strains antigenically similar to those present in the vaccine.
• Efficacy is variable and depends on the degree of similarity between vaccine strains and circulating strains of influenza virus. Under optimal conditions of timing and strain relatedness, the incidence of disease may be reduced by 70% in healthy younger adults.
• Protection is transient, and yearly immunization is necessary irrespective of whether significant antigenic changes in the prevailing strains have occurred. Adequate protection is generally achieved in immunologically primed healthy individuals who receive a single dose, and the vaccine is most effective when it precedes exposure by no more than 2–4 mos.
• Immunogenicity is variable among immunocompromised individuals. Successful immunologic responses in these populations are most likely to occur when immunized individuals have previously been primed by exposure to antigenically similar influenza strains.
LAIV
• In 1985, a controlled trial comparing one candidate LAIV for strains A(H1N1) and A(H3N2) to a trivalent inactivated vaccine was initiated. A total of 5,210 subjects aged 1–65 yrs were enrolled.
• Efficacy of the live and inactivated vaccines against culture-proved influenza A(H1N1) was 85% and 76%, respectively, and efficacy against influenza A(H3N2) was 58% and 74%, respectively. Efficacy in vaccinees aged <16 yrs was somewhat better but still comparable. Some studies do show, however, better and longer-lasting efficacy of LAIV in children as compared to that of inactivated vaccine.
• In experiments using LAIV as a challenge, subjects previously immunized with LAIV shed less virus than those previously immunized with inactivated vaccine. These results suggest that LAIV may reduce carriage of natural influenza virus and help to control spread of infection in the community.
• In an open-label study in central Texas, >16,000 children aged between 18 mos and 18 yrs are targeted for immunization with LAIV to determine whether herd immunity will be operative.
• In a controlled study of seronegative adults who were subsequently challenged with wild-type viruses, efficacy of trivalent LAIV against infection was 85%, and efficacy of inactivated vaccine was 71%. Trivalent LAIV was also evaluated in a multicenter placebo-controlled study involving 1,602 children aged 15–71 mos; most of them received 2 doses 60 days apart. Efficacy was 93% against culture-proved influenza A(H3N2) and B [there was no circulation of influenza A(H1N1)]. Febrile otitis media, antibiotic usage, and medical visits were also reduced.
• Approximately 85% of the subjects returned for vaccination the next year, when the circulating influenza A virus was A/Sydney/5/97-like (H3N2) [the vaccine contained A/Wuhan/359/95 (H3N2)]. Despite the mismatch between vaccine and circulating strains, efficacy against influenza A that year was 92%, indicating cross-strain protection. Efficacy against pneumonia, other lower respiratory tract disease, and influenza-associated otitis media was also demonstrated.
• To test for efficacy against influenza A(H1N1), vaccinated children were challenged with a monovalent cold-adapted strain. LAIV provided 83% protection against nasopharyngeal shedding of the challenge virus.