Commercial Influenza Vaccine Research Articles

Analysis of the quality of protection induced by a porcine influenza A vaccine to challenge with an H3N2 virus

Antigenic drift of swine influenza A (H3N2) viruses away from the human A/Port Chalmers/1/73 (H3N2) strain, used in current commercial swine influenza vaccines, has been demonstrated in The Netherlands and Belgium. Therefore, replacement of this human strain by a more recent swine H3N2 isolate has to be considered. In this study, the efficacy of a current commercial swine influenza vaccine to protect pigs against a recent Dutch field strain (A/Sw/Oedenrode/96) was assessed. To evaluate the level of protection induced by the vaccine it was compared with the optimal protection induced by a previous homologous infection. Development of fever, virus excretion, and viral transmission to unchallenged group mates were determined to evaluate protection. The vaccine appeared efficacious in the experiment because it was able to prevent fever and virus transmission to the unchallenged group mates. Nevertheless, the protection conferred by the vaccine was sub-optimal because vaccinated pigs excreted influenza virus for a short period of time after challenge, whereas naturally immune pigs appeared completely protected. The immune response was monitored, to investigate why the vaccine conferred a sub-optimal protection. The haemagglutination inhibiting and virus neutralising antibody responses in sera, the nucleoprotein-specific IgM, IgG, and IgA antibody responses in sera and nasal secretions and the influenza-specific lymphoproliferation responses in the blood were studied. Vaccinated pigs developed the same or higher serum haemagglutination inhibiting, virus neutralising, and nucleoprotein-specific IgG antibody titres as infected pigs but lower nasal IgA titres and lymphoproliferation responses. The lower mucosal and cell-mediated immune responses may explain why protection after vaccination was sub-optimal.

Efficacy of vaccination of pigs with different H1N1 swine influenza viruses using a recent challenge strain and different parameters of protection

This study investigates whether antigenic evolution within H1N1 swine influenza viruses can compromise vaccine efficacy and, specifically, whether the A/New Jersey/8/76 strain in the commercial swine influenza vaccines needs to be updated. Pigs were vaccinated twice intramuscularly with experimental monovalent vaccines derived from different H1N1 strains (A/New Jersey/8/76, Sw/Belgium/1/83 or Sw/Belgium/1/98) or with a commercial bivalent vaccine based on A/New Jersey/8/76 (H1N1) and A/Port Chalmers/1/73 (H3N2). Experimental and commercial vaccines contained a different adjuvant. Two weeks after the second vaccination, all pigs were challenged intratracheally with Sw/Belgium/1/98. Mean pre-challenge haemagglutination inhibition (HI) antibody titres against the challenge virus were lower for the experimental A/New Jersey/8/76 vaccine than for the other vaccines. The reduction in mean virus titres in the lungs was highly significant for the latter vaccines, including the commercial New Jersey-derived vaccine, but not for the experimental A/New Jersey/8/76 vaccine. Clinical signs after challenge were negligible in all vaccinates. Post-challenge levels of interferon-α and tumor necrosis factor-α in bronchoalveolar lavage fluids were reduced in the vaccinates, while levels of interleukin-1 and neutrophils were less consistent. Though the A/New Jersey/8/76 strain is less effective in preventing infection by Sw/Belgium/1/98 than the homologous virus or than Sw/Belgium/1/83, all strains can protect completely if antibody titres against the challenge virus are sufficiently high. Apart from the vaccine strain, adjuvant and antigenic dose may play a crucial role in vaccine efficacy.

Acceptable protective efficacy of influenza vaccination in young military conscripts under circumstances of incomplete antigenic and genetic match

Commercial inactivated parenteral influenza vaccines reduced febrile (≥38°C) respiratory illness by 53% (95% CL: 41–63%) during a 3 week outbreak in 1998 when A/Sydney/5/97(H3N2)-like influenza viruses were shown to be the predominant etiological agents and an older antigenic variant, A/Nanchang/933/95, served as the vaccine virus. The calculatory efficacy for preventing virologically diagnosed influenza infections was 57% (95% CL: 40–68%). The study population consisted of 1374 young male military conscripts. Vaccination coverage on a voluntary basis was 67%. Vaccination was ineffective in preventing febrile illness during a second epidemic wave lasting 2 weeks when mainly adenoviruses were shown to have been circulating in the garrison. Out of the 36 nasopharyngeal aspirates positive for influenza A by antigen detection, 18 A/Sydney/5/97-like strains (10 from non-vaccinated and eight from vaccinated subjects) and two A/Nanchang/933/95-like strains (both from non-vaccinated subjects) were isolated in MDCK cell cultures. Intraepidemic variation was detected among the A/Sydney/5/97-like field strains in their HA1 sequences and reactivity in HI tests, but no evidence was obtained that this variation would have been of significance to the virus in breaking through the vaccination-induced immunity.

Efficacy of influenza vaccination in adult liver transplant recipients

To assess the efficacy of influenza vaccination in immunocompromised adult liver transplant (LTx) recipients, the serum antibody responses of 61 of these patients and 35 liver cirrhosis patients with those of 45 of their healthy spouses were compared, after one and two vaccinations with a commercial trivalent subunit influenza vaccine. In addition, virus-specific proliferative T-cell responses were measured in LTx recipients and their healthy spouses. In all three study groups, significant rises in geometric mean antibody titers were observed for all three antigens after one vaccination. These titers did not continue to increase significantly after the second vaccination in patients with cirrhosis and control subjects but did rise for LTx recipients. The overall antibody response to all three influenza virus strains proved to be significantly lower in the LTx recipients than in the group of healthy subjects after both one and two vaccinations. More than 68% of the LTx recipients developed hemagglutination-inhibiting serum antibody titers >/=40 against all three vaccine strains after the first vaccination and more than 80% after the second vaccination. These findings correlated with the T-cell responses determined for the group of LTx recipients and healthy control individuals. Testing of the respective serum samples against influenza virus A/Sydney/5/97, which circulated in the 1997-1998 influenza season and showed a considerable mismatch with the vaccine strain A/Nanchang/933/95, indicated that such a mismatch may have significant consequences for vaccine efficacy, especially for LTx recipients. Collectively the data show that LTx recipients can be vaccinated effectively against influenza despite immunosuppressive therapy. A two-dose vaccination regimen improved vaccination efficacy in LTx recipients. Whether transplant patients generally benefit from a two-dose vaccination regimen should be evaluated further.

Reactogenicity in the elderly of nine commercial influenza vaccines: results from the Italian SVEVA study

A 10-fold increase of reported adverse events following influenza vaccination in the 1995–1996 campaign was reported. To evaluate the relative reactogenicity of different influenza vaccines a prospective observational study was conducted in 72 Italian local health units (LHU) in the period October–December 1996. Of the 16,637 enrolled individuals aged 65 or more, 27.4% reported the occurrence of at least one adverse event within 72 h of vaccination. The odds ratios, adjusted through a multivariate logistic model, were highest for whole vaccine recipients. Most of the observed events were of moderate clinical severity and were mainly represented by local symptoms. None of the products was found to show an unusual or concerning reactogenicity profile, and no severe events associated with immunization were reported.

The adjuvants MF59 and LT-K63 enhance the mucosal and systemic immunogenicity of subunit influenza vaccine administered intranasally in mice

Commercial influenza vaccines generate serum antibody, but not local IgA. Influenza vaccines that induce both serum and secretory antibody are more likely to protect against infection and disease progression. The adjuvants MF59 and LT-K63 were tested intramuscularly and intranasally with subunit HA. In naive mice, intranasal adjuvant effect was more apparent when included with the first than second immunization. In previously infected mice, intranasal adjuvants had little effect on serum antibodies and were most effective for nasal antibodies after the second immunization. Overall, both adjuvants enhanced anti-HA IgA and IgG by intranasal vaccination whereas, by intramuscular vaccination, they only enhanced serum IgG.

Poly[di(carboxylatophenoxy)phosphazene] (PCPP) is a potent immunoadjuvant for an influenza vaccine

The adjuvant activity of poly[di(carboxylatophenoxy)phosphazene] (PCPP) on the immunogenicity of formalin-inactivated influenza virions and commercial trivalent influenza vaccine was studied. Regardless of which antigen preparation is used, the addition of 100 μg PCPP enhances the HAI antibody response 10-fold over the levels elicited by the vaccine alone. Similarly, PCPP enhanced the IgM, IgG, and IgG1 ELISA antibody titers to influenza antigens at least 10-fold higher than the vaccine alone. In contrast, the IgG2a isotype titers were only enhanced about 2-fold. Immunization of aged mice (22 months old) with trivalent influenza vaccine alone did not sero-convert these mice as measured by HAI or ELISA whereas significant sero-conversion was achieved when mice were immunized with PCPP-formulated trivalent vaccine. The adjuvant activity of PCPP was shown to not be due to a site of injection depot effect. PCPP adjuvanticity was positively correlated to the molecular weight of the polymer.

Immunogenicity of trivalent subunit versus virosome-formulated influenza vaccines in geriatric patients

The safety and immunogenicity of a commercial trivalent subunit influenza vaccine and an experimental virosome-formulated influenza vaccine were evaluated among geriatric patients in a double-blind, randomized manner. The virosome vaccine was produced by incorporating hemagglutinin (HA) into the membrane of liposomes composed of phosphatidylcholine. Both vaccines elicited a significant ( P < 0.01) rise in the geometric mean anti-HA antibody titer to all three vaccine components 1 month after immunization. However, significantly ( P < 0.005) more subjects vaccinated with the virosome preparation mounted a more than fourfold rise to the A/Singapore and A/Beijing strains compared with those who received subunit vaccine. The percentage of patients who attained protective levels (anti-HA titer ≥ 40) of anti-A/Beijing antibody was also significantly ( P < 0.005) higher in the virosome group. Subjects who possessed non-protective baseline antibody levels to the A/Singapore and A/Beijing strains were more likely ( P < 0.005–0.030) to achieve protective levels after immunization with the virosome vaccine than with the subunit vaccine. Of particular clinical significance was the fact that 68.4% of subjects immunized with the virosome vaccine attained protective levels of antibody to all three vaccine components versus 38% for the subunit vaccine ( P = 0.010).

Cross-reaction but no avidity change of the serum antibody response after influenza vaccination

Pre- and post-vaccination sera from 19 volunteers were analysed by the haemagglutination inhibition (HI) test, virus neutralization (VN) assay and avidity enzyme-linked immunosorbent assay (ELISA). The sera were tested against the three strains in a commercial inactivated influenza vaccine; A/Beijing/353/89(H3N2); A/Taiwan/1/86(H1N1) and B/Yamagata/16/88. Additionally, a range of earlier strains and one newer isolate were assayed for HI- and VN-antibodies. Large variations in the pre-vaccination HI titres were observed for the viruses tested. However, 8–9 days after vaccination HI titres increased to above the assumed protective level (HI ⩾ 40) in most subjects. Although a limited number of aptients were analysed at each sampling point, the time-profile we observed in this study is consistent with data we have obtained in earlier trials (Cox, R.J. et al., Vaccine 1994, 12, 993–999). The VN titres, on the other hand, were low against all influenza strains before and up to 6 days, but increased rapidly 8–9 days after vaccination. A recent H3N2 isolate, A/Beijing/32/92(H3N2), which had drifted further away from the vaccine strain, reacted to low titres or were negative in both the HI and VN assays. No change in the serum avidity to the influenza surface antigens was detected after vaccination, whereas sera from subjects naturally infected with influenza showed an increase in avidity to the infecting virus strain. The increase in serum avidity observed in the infected subjects is probably due to the increased and prolonged antigenic stimulus provided by the replicating virus.

High doses of purified influenza A virus hemagglutinin significantly augment serum and nasal secretion antibody responses in healthy young adults

The reactogenicity and immunogenicity of purified influenza virus hemagglutinin (HA) vaccines administered intramuscularly were evaluated in two placebo-controlled clinical trials. A total of 139 healthy young adults were randomized to receive increasing doses of monovalent influenza A/Taiwan/1/86 (H1N1) virus HA (range, 0 to 405 micrograms per dose [study 1]). An additional 139 subjects were given increasing doses of a trivalent HA vaccine containing equal amounts of A/H1N1 virus, A/Shanghai/16/89 (H3N2) virus, and influenza B/Yamagata/16/88 virus HA (range, 0 to 135 micrograms of HA per strain, 0 to 405 micrograms per dose) or a standard dose of commercial influenza vaccine (study 2). Increasing doses of HA were associated with increasing frequencies of symptoms at the vaccination site early after vaccination, but all doses were well tolerated. Occurrence of systemic symptoms was unrelated to dose. Increasing the dose of HA resulted in increasingly higher postimmunization levels of serum hemagglutination inhibiting and neutralizing antibody levels versus influenza A/H1N1 virus in study 1 (P < 0.05); these enhanced responses persisted for up to 6 months. Nasal secretory immunoglobulin A and G antibody responses were assessed 2 weeks after immunization with monovalent H1N1 virus HA; the frequencies of significant responses also increased in a dose-related fashion. Similar increases in serum antibody levels were noted for both A/H1N1 and A/H3N2 viruses in study 2. These data provide a basis for proceeding with the evaluation of high doses of purified HA in the elderly.

HI antibody kinetics in adult volunteers immunized repeatedly with inactivated trivalent influenza vaccine in 1990-1992.

Volunteers were immunized once, twice or three times in 1990-1992 with commercial trivalent inactivated influenza vaccine and monitored for haemagglutination inhibition (HI) antibodies. The antibodies that already existed when the subjects entered the study derived from natural infections. Immunizations in the second and third years were necessary to maintain the geometric mean titres of antibody and protection rates at the level recorded after the first vaccination. Negative correlations between prevaccination antibody titres and mean fold antibody increases were noted in most instances analysed. Moreover, at each individual prevaccination titre level the mean fold antibody increases and even postvaccination mean titres were higher after the first than after subsequent vaccinations, suggesting that the HI antibody responses might be affected by vaccine-induced pre-existing antibody more than by the same titres of antibody derived from natural infections. This was most obvious for antibody to the H1N1 subtype virus, A/Finland/164/91. In immunization with B/Yamagata/16/88, anamnestic response of antibody to B/Finland/150/90, which belongs to the antigenically distinct lineage of B/Victoria/2/87-like viruses, was more frequent in the first than in subsequent years. This is in contrast to homologous antibodies, which increased significantly after the second vaccination.

Local and systemic influenza haemagglutinin-specific antibody responses following aerosol and subcutaneous administration of inactivated split influenza vaccine

An easily administered and safe vaccine is required to produce the herd immunity necessary to control influenza epidemics worldwide. A commercial quadrivalent inactivated split influenza vaccine was administered intranasally in aerosol form to a group of 46 volunteers; other groups were given the same vaccine subcutaneously and saline intranasally. The results show that mucosal stimulation via intranasal vaccination resulted in a marked increase in local HA-specific IgA antibodies, and that this stimulation was necessary for serum HA-specific IgA responses. Serum HA-specific IgA antibody levels can be used as indicators of local antigenic stimulation, providing a method for evaluating potency and antigenicity in humans of intranasal influenza vaccine. This vaccination route shows much promise for the future.

Antibody Responses to Influenza B Viruses in Immunologically Unprimed Children

The cocirculation in several parts of the world of influenza viruses B/Yamagata/16/88 and B/Victoria/2/87, which are genetically and antigenically divergent, has prompted the question of whether immunization with one viral antigen is sufficient for protection against both strains. Twenty-three high-risk infants and young children were immunized with a commercial trivalent influenza vaccine containing the antigens of influenza virus B/Yamagata/16/88. When antibodies against influenza viruses B/Yamagata/16/88 and B/Victoria/2/87 were determined, increases developed uniformly to both in the sera of primed children previously exposed to influenza virus B/Victoria/2/87 by immunization or infection. Antibodies against B/Yamagata/16/88 developed in the sera of unprimed children with titers similar to those of the primed children. However, antibodies to B/Victoria/2/87 were not detected in the sera of the unprimed children. These data suggest that children without appropriate immunologic priming may not be protected against an infection with a B/Victoria/2/87 strain after vaccination with a B/Yamagata/16/88 strain. Immunization with more than one influenza B virus strain may be desirable in some high-risk pediatric patients if divergent influenza B viruses circulate.

Failure of influenza vaccination in the aged.

A cohort of 127 nursing home residents aged 60-98 years were vaccinated during the winter of 1985-86 with the A-Chile 1/83 (C), A-Philippines 2/82 (P), and B-USSR (B) commercial influenza vaccines. Before vaccination 40%, 23%, and 69% were susceptible to influenza Ac, Ap, and B, respectively [hemagglutinin inhibition (H.I.) titer less than 1:40]. One month following initial vaccination, 32 patients [25%] remained unprotected against two or all three vaccine strains. These patients were revaccinated with the same influenza vaccine and followed up. At five months 11%, 19%, and 23% of the initial cohort were still unprotected against Ac, Ap, and B strains, respectively. We conclude that two conventional influenza vaccines administered one month apart leave unprotected 30% of healthy elderly people who are initial influenza vaccine failures.

The estimation of host antigen in experimental and commercial influenza subunit preparations by delayed-type hypersensitivity reaction

A delayed-type hypersensitivity (DTH) test has been used to detect the presence of host-specific antigen(s) in highly-purified egg-grown influenza virus and virus components. Cyclophosphamide-treated mice, primed with an extract from allantoic fluid, showed DTH reactions when challenged with whole virus, spikeless virus particles or polymer-type subunits. All commercial egg-grown influenza vaccines showed the presence of host antigen, whereas lipid-free derivatives such as internal virus protein complexes and monomer HA preparations lacked the activity. These findings are discussed in relation to vaccine application.

Impaired serum antibody response to inactivated influenza A and B vaccine in renal transplant recipients

Before and after vaccination with a commercial inactivated influenza vaccine containing A/Aichi/2/68 (H3N2) and B/Massachusetts/1/71 antigens, the serum hemagglutination inhibition antibody titers to homologous and heterologous strains of A and B influenza viruses were measured in 45 renal transplant patients and 66 healthy controls (62 for the B strains). At least a fourfold titer rise to the homologous A strain occurred in 14 of 45 transplant patients (31%) versus 37 of 66 controls (56%). Fourfold or greater heterologous A rises occurred in only 8 of 45 transplant patients (18%) compared with 40 of 60 controls (61%). In both the homologous and heterologous B responses, at least fourfold hemagglutination inhibition titer rises were seen in significantly fewer transplant patients than control subjects. In the transplant group, no correlation was observed between degree of antibody response and age, previous influenza vaccination, percentage of patients initially seronegative, time since transplantation, dose of immunosuppressive drugs, level of renal function, or nature of original renal disease.

An assessment of oil adjuvant and aqueous influenza vaccines. II. Antibody responses to the vaccines.

In trials with polyvalent commercial influenza vaccines the antibody responses to oil-adjuvant vaccine persisted longer and were often higher. Antibody conversion was poor after all vaccines and delayed after adjuvant.

Acute vascular purpura following immunization with Asiatic-influenza vaccine.

THIS paper describes the occurrence of acute vascular purpura in a patient who received polyvalent Asiatic-influenza vaccine. The vasculitic process appeared to be due to an antigen–antibody reaction, the antibody being presumably formed in response to the antigenic stimulus of the vaccine. Because of the apparent rarity of this complication, it was believed that its reporting might call attention to similar cases and alert physicians to such a possibility.Case ReportMiss M. R., a 37-year-old secretary, received intradermally in each deltoid area 1 ml. of a commercial polyvalent influenza vaccine** on October 28, 1957. Three days later blepharoconjunctivitis developed . . .