Evaluation of live and inactivated influenza A virus vaccines in a mouse model

Induction of cross-protective immunity against serologically distinct subtypes of influenza A virus in mice was examined in an attempt to correlate cross-protection with heterotypic lymphocyte responses. Live and inactivated virus vaccines protected against the homologous subtype, but only whole virus protected against heterologous subtypes. Live virus vaccines provided better cross-protection than inactivated virus vaccines. A weak defense against heterotypic challenge generated by live H0N1 virus could be boosted by cross-stimulation with whole H3N2 virus and by restimulation with pathogenic H0N1 virus. Heterotypic protection persisted for at least five months. Live viruses induced cross-reactive cytotoxic T cells in normal mice. However, cross-stimulation with heterologous virus was required to generate secondary cytotoxicity. Cross-reactive B lymphocytes were evident after inoculation with whole virus.     

Use of influenza A virus vaccines in seronegative children: live cold-adapted versus inactivated whole virus

We report the safety and antigenicity of influenza A vaccines in seronegative children one to seven years of age. A natural H1N1 challenge that occurred shortly after completion of the vaccination program permitted an evaluation of efficacy. Twenty-eight subjects were inoculated with live cold-adapted (ca) influenza A/Washington/897/80 (H3N2), 29 with ca influenza A/California/10/78 (H1N1), 24 with inactivated whole-virus influenza A/Bangkok/79 (H3N2), and 30 with a placebo. The ca vaccines were well tolerated, whereas the inactivated vaccine caused adverse reactions in about one-third of the children. Fifty-seven percent of the ca H1N1 recipients showed serological responses, contrasted with 84% and 100% of subjects receiving the ca or inactivated H3N2 vaccines, respectively. None of the 16 children with induced H1N1 antibody developed clinically apparent influenza-like illness, compared with eleven of the 51 initially seronegative children who did not receive the ca H1N1 vaccine and with four of the 12 who failed to respond. Results of the efficacy field trial suggest protection against infection and symptomatic illness in children inoculated with ca H1N1, despite its failure to stimulate high levels of hemagglutinin-inhibiting antibody.     

The relative efficacy of trivalent live attenuated and inactivated influenza vaccines in children and adults

In the United States, two types of vaccines are recommended for the prevention of influenza: an intranasal live attenuated influenza vaccine (LAIV) for eligible individuals aged 2-49 years and unadjuvanted injectable trivalent inactivated vaccines (TIV) for eligible individuals aged ≥ 6 months. Several recent studies have compared the efficacy of the 2 vaccines in children and adults. In children 6 months to 18 years of age, each of the four comparative studies of LAIV and TIV demonstrated that LAIV was more protective. In individuals 17-49 years of age, most comparative studies have demonstrated that LAIV and TIV were similarly efficacious or that TIV was more efficacious. However, LAIV was shown to be more protective than TIV in new military recruits of all ages, and placebo-controlled studies in adults in 1997-1998 suggested that LAIV was more protective against the mismatched A/H3N2 strain. The relative efficacy of LAIV and TIV among young adults may vary depending on the specific population and the antigenic match between the vaccines and circulating strains. In adults 60 years of age and older, limited data suggest that the two vaccines are similarly effective. In children and adults, studies also suggest that the relative efficacy of LAIV versus TIV may increase when measured against more severe illness. Additional research comparing LAIV and TIV is needed in adults and would also be valuable in older children and adolescents. Studies should examine the role of pre-existing immunity as well as vaccine impact on influenza illness of varying severity.     

Superiority of live attenuated compared with inactivated influenza A virus vaccines in older, chronically ill adults

Forty-eight older adults with chronic diseases were vaccinated intranasally with live attenuated influenza A/Korea/1/82 (H3N2), CR59 virus. Forty-two (88 percent) CR59 virus recipients became infected with vaccine virus without adverse effects or change in mean pulmonary function even among the 29 infected recipients with moderate to severe chronic obstructive pulmonary disease. Among control groups who received either monovalent or trivalent inactivated influenza virus vaccines intramuscularly, the rates of fourfold rises in serum antibody titer to hemagglutinin (HA) were not different from the rate following CR59 virus inoculation. However, CR59 virus was superior to inactivated virus vaccine at stimulating secretory antibody to HA. Vaccinees age 65 years and older were more likely to shed CR59 virus in nasal secretions than were younger vaccinees, but antibody responses were not different. CR59 virus vaccine was safe and immunogenic in this population and more often induced a nasal wash IgA antibody response than the inactivated virus vaccines.     

Pilot studies on recombinant cold-adapted live type A and B influenza virus vaccines.

Recombinant live attenuated type A and B influenza virus vaccines derived from standardized cold-adapted parent strains were given singly and in combination to volunteers. The vaccine viruses were well tolerated, functioned as good antigens, and failed to spread to intimate household contacts. Thirty-nine isolates that were recovered after a single passage in humans appeared genetically stable. The results of histopathologic studies in ferrets encourage development of an animal model for attenuation of the virus.     

Prevention of symptomatic seasonal influenza in 2005-2006 by inactivated and live attenuated vaccines

BACKGROUND: The efficacy of influenza vaccines may vary annually. In 2004-2005, when antigenically drifted viruses were circulating, a randomized, placebo-controlled trial involving healthy adults showed that inactivated vaccine appeared to be efficacious, whereas live attenuated vaccine appeared to be less so. METHODS: In 2005-2006, we continued our trial, examining the absolute and relative efficacies of the live attenuated and inactivated vaccines in preventing laboratory-confirmed symptomatic influenza. RESULTS: A total of 2058 persons were vaccinated in October and November 2005. Studywide influenza activity was prolonged but of low intensity; type A (H3N2) virus was circulating, which was antigenically similar to the vaccine strain. The absolute efficacy of the inactivated vaccine was 16% (95% confidence interval [CI], -171% to 70%) for the virus identification end point (virus isolation in cell culture or identification through polymerase chain reaction) and 54% (95% CI, 4%-77%) for the primary end point (virus isolation or increase in serum antibody titer). The absolute efficacies of the live attenuated vaccine for these end points were 8% (95% CI, -194% to 67%) and 43% (95% CI, -15% to 71%), respectively. CONCLUSIONS: With serologic end points included, efficacy was demonstrated for the inactivated vaccine in a year with low influenza attack rates. The efficacy of the live attenuated vaccine was slightly less than that of the inactivated vaccine, but not statistically greater than that of the placebo.     

Pulmonary and serum isotypic antibody responses of mice to live and inactivated influenza virus

Primary and secondary immunoglobulin class-specific antibody responses in serum and pulmonary lavage fluids of mice were studied after respiratory infection and intramuscular vaccination with influenza virus. Infection and vaccination with inactivated virus vaccine induced primary IgM and IgG antibody responses in the serum and pulmonary lavage fluids (PLF). Neither immunizing method induced detectable serum IgA antibodies, and only infection generated IgA antibodies in PLF. The major portion of antibodies in PLF was derived from serum, but local synthesis of IgG and IgA antibodies was detected after virus infection. Vaccination of infection-primed mice boosted the IgM and IgG antibody concentrations in serum and PLF but had no effect on IgA antibody concentrations. Nonlethal infection of vaccine-primed mice generated secondary IgM and IgG antibody responses in serum and PLF and an IgA antibody response in PLF. Again, most of the antibody detected in PLF was derived from serum, but low concentrations of IgA and IgG were synthesized locally after infection. Although mice immunized with inactivated vaccine lacked the capacity to synthesize IgA antibody, they were protected from severe pulmonary disease when challenged with lethal influenza virus. These data support the concept that serum IgG antibodies are sufficient for prevention of severe pulmonary disease.     

Cross-protection against H5N1 influenza virus infection is afforded by intranasal inoculation with seasonal trivalent inactivated influenza vaccine

BACKGROUND: Avian H5N1 influenza A virus is an emerging pathogen with the potential to cause substantial human morbidity and mortality. We evaluated the ability of currently licensed seasonal influenza vaccine to confer cross-protection against highly pathogenic H5N1 influenza virus in mice. METHODS: BALB/c mice were inoculated 3 times, either intranasally or subcutaneously, with the trivalent inactivated influenza vaccine licensed in Japan for the 2005-2006 season. The vaccine included A/NewCaledonia/20/99 (H1N1), A/NewYork/55/2004 (H3N2), and B/Shanghai/361/2002 viral strains and was administered together with poly(I):poly(C(12)U) (Ampligen) as an adjuvant. At 14 days after the final inoculation, the inoculated mice were challenged with either the A/HongKong/483/97, the A/Vietnam/1194/04, or the A/Indonesia/6/05 strain of H5N1 influenza virus. RESULTS: Compared with noninoculated mice, those inoculated intranasally manifested cross-reactivity of mucosal IgA and serum IgG with H5N1 virus, as well as both a reduced H5N1 virus titer in nasal-wash samples and increased survival, after challenge with H5N1 virus. Subcutaneous inoculation did not induce a cross-reactive IgA response and did not afford protection against H5N1 viral infection. CONCLUSIONS: Intranasal inoculation with annual influenza vaccine plus the Toll-like receptor-3 agonist, poly(I):poly(C(12)U), may overcome the problem of a limited supply of H5N1 virus vaccine by providing cross-protective mucosal immunity against H5N1 viruses with pandemic potential.     

Efficacy of inactivated influenza A virus (H3N2) vaccines grown in mammalian cells or embryonated eggs

Influenza virus (H3N2) host cell variants isolated from a single infected individual were compared for their protective efficacies when used as formalin-inactivated purified whole virus vaccines in ferrets. A/Mem/12/85 virus grown in embryonated chicken eggs (egg-grown), which differs from A/Mem/12/85 grown in mammalian Madin-Darby canine kidney cells (MDCK-grown) by a single amino acid substitution in the hemagglutinin molecule, was shown to be distinguishable by immune ferret serum. Ferrets were immunized intramuscularly with intact inactivated MDCK- or egg-grown virus and were subsequently challenged with infectious virus grown in either host cell type. MDCK-grown-virus vaccine induced higher mean serum hemagglutination-inhibiting (HAI) and neutralizing antibody titers than did egg-grown-virus vaccine and induced superior protection of ferrets against subsequent challenge with infectious virus grown in either host cell type. These results suggest that human influenza viruses that are antigenically and structurally similar to viruses grown in mammalian cells may be more efficacious as vaccines than some variants selected in eggs.     

Immunogenicity of inactivated influenza vaccine in residential homes for elderly people.

One hundred and seventy residents of 11 Leicester City Council homes for the elderly, with a total of 515 beds, were studied during a 30-week period from September 1988 to March 1989 to determine the use of influenza vaccine, the levels of influenza antibody, the incidence of influenza, and the protection afforded by vaccination. The study group of 133 women and 37 men had a mean age of 85 years and 59% had one or more chronic medical conditions. The immunization rates by home for the 170 symptomatic residents ranged from 8% to 90% (mean 45%). Seventy-one sera, 36 from vaccinated and 35 from non-vaccinated residents were collected between 1 December 1988 and 24 March 1989 and were assayed for antibody to A/Taiwan/1/86 (H1N1), A Sichuan/2/87 (H3N2) and B/Beijing/1/87. Analysis revealed no statistically significant differences between the antibody profiles of vaccinated and unvaccinated subjects. Six influenza A and 6 influenza B infections were confirmed among the 170 subjects with upper respiratory tract infections. Influenza vaccination was not associated with significant levels of protection against influenza A or B. Studies of the haemagglutinins of the vaccine strains and influenza isolates during 1988/89 showed that they were closely related.     

Construction of live vaccines by using genetically engineered poxviruses: biological activity of recombinant vaccinia virus expressing influenza virus hemagglutinin.

Recombinant vaccinia viruses containing the cloned hemagglutinin (HA) gene from influenza virus were constructed. The biological activity of these poxvirus vectors was demonstrated both in vitro and in vivo. Expression of HA in cells infected with recombinant vaccinia was detected by using specific anti-HA antiserum and 125I-labeled protein A, showing that HA synthesized under the regulation of vaccinia virus was antigenic. Immunization of rabbits with these recombinant poxviruses resulted in the production of antibodies reactive with authentic influenza HA as detected by radioimmunoassay, by inhibition of HA erythrocyte agglutination, and by neutralization of influenza virus infectivity. The production of antibodies directed against influenza HA suggested that the HA gene expressed in vaccinia is immunogenic. These data indicate the potential of genetically engineered poxviruses for use as generic live vaccine vehicles that have both human and veterinary applications.     

Immunization against influenza: comparison of various topical and parenteral regimens containing inactivated and/or live attenuated vaccines in healthy adults

Methods for enhancing immune responses to influenza were explored in 2 double-blind, placebo-controlled trials. Intranasal (inl) immunization with monovalent, live attenuated, cold-adapted recombinant (CR) or inactivated influenza virus (MIV) vaccine and intramuscular (im) immunization with MIV were evaluated in various combinations. Healthy susceptible adults were assigned randomly to receive 10(7.1) TCID(50) of CR (A/H1N1 or A/H3N2), homologous MIV (15 microg), or placebo inl and placebo or homologous MIV im (6 groups in each study). Serum antibody responses were greatest in groups given im vaccine (with or without inl vaccine). A 2-fold increase in nasal wash antibody response frequencies was seen in groups given combined inl (CR or MIV) and im vaccine, compared with subjects given a single im (MIV) or inl (CR or MIV) vaccine. Combined inl and im immunization is a promising approach for enhancing both local and systemic immune responses against influenza.     

Quantitative review of antibody response to inactivated seasonal influenza vaccines

Please cite this paper as: Seidman et al. (2012) Quantitative review of antibody response to inactivated seasonal influenza vaccines. Influenza and Other Respiratory Viruses 6(1), 52–62. Background Seasonal influenza epidemics are associated with significant morbidity and mortality each year, particularly amongst young children and the elderly. Seasonal influenza vaccines have been available for decades, yet influenza remains a major public health threat in the US, sparking interest in studies evaluating the effectiveness of vaccination. Objectives We sought to identify determinants of serological responses to inactivated seasonal influenza vaccines including number of doses, adjuvant, and subject characteristics. Methods We reviewed 60 articles published between 1987 and 2006. We used weighted multiple logistic regression and random‐effects models to evaluate how seroconversion and seroprotection rates varied with host and vaccine factors. Results Both children and seniors tended to have poorer immune responses compared to adults whereas use of adjuvant and a second vaccine dose tended to improve immune response. Pre‐vaccination serological status had a large impact on the immune response to vaccination. We found substantial heterogeneity among studies, even with similar population settings and vaccination regimen. Conclusions Future studies should stratify their results by pre‐vaccination serological status in an effort to produce more precise summary estimates of vaccine response.     

Antibody response to inactivated influenza vaccines of various antigenic concentrations

Four inactivated influenza vaccines (containing the recommended antigens for the 1985-1986 influenza season) of various antigenic concentration levels were randomly administered to 140 study participants. The effect of the increasing antigen concentration resulted in significantly higher influenza hemagglutination inhibition (HI) antibody levels 3 weeks after vaccination for the A/H1N1 antigen but not for the A/H3N2 or B antigens. Also, at 3 weeks after vaccination, there were significantly lower antibody titer levels associated with increasing age for the A/H1N1 and B antigens (adjusting for the prevaccination antibody titer and antigen content).     

Studies of prototype live hepatitis A virus vaccines in primate models

We have prepared two prototype live hepatitis A virus (HAV) vaccines by serial passage of the HM-175 strain of HAV in African green monkey kidney cells. Passage 21 (P-21) HM-175 virus shows evidence of attenuation for chimpanzees but not for marmosets; passage 32 (P-32) HM-175 virus shows evidence of attenuation for both species. Animals that received P-32 HAV had fewer elevations in levels of liver enzyme activity and evidence of less virus replication in the liver and excretion of virus in stool than did those that received wild-type virus. The P-21 and P-32 viruses were highly immunogenic in both species. The information provided by this study will aid in the development of a live HAV vaccine.     

Comparative immunogenicity and cross-clade protective efficacy of mammalian cell-grown inactivated and live attenuated H5N1 reassortant vaccines in ferrets

Continued H5N1 virus infection in humans highlights the need for vaccine strategies that provide cross-clade protection against this rapidly evolving virus. We report a comparative evaluation in ferrets of the immunogenicity and cross-protective efficacy of isogenic mammalian cell-grown, live attenuated influenza vaccine (LAIV) and adjuvanted, whole-virus, inactivated influenza vaccine (IIV), produced from a clade 1 H5N1 6:2 reassortant vaccine candidate (caVN1203-Len17rg) based on the cold-adapted A/Leningrad/134/17/57 (H2N2) master donor virus. Two doses of LAIV or IIV provided complete protection against lethal homologous H5N1 virus challenge and a reduction in virus shedding and disease severity after heterologous clade 2.2.1 H5N1 virus challenge and increased virus-specific serum and nasal wash antibody levels. Although both vaccines demonstrated cross-protective efficacy, LAIV induced higher levels of nasal wash IgA and reduction of heterologous virus shedding, compared with IIV. Thus, enhanced respiratory tract antibody responses elicited by LAIV were associated with improved cross-clade protection.