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Abstract: The correlates for protection against influenza infection are incompletely characterized. We have applied an ELISA strategy that distinguishes antibodies against native viral surface antigens (potentially neutralizing) from antibodies directed against internal and denatured viral proteins (not neutralizing) to three groups of vaccinated subjects: (1) participants in a study of repeated annual vaccination, (2) elderly subjects and (3) patients with Systemic Lupus Erythematosus compared to control subjects. Antibody increase after vaccination was inversely related to the level of pre-existing antibodies in all groups; most subjects had significant initial antibody levels and showed little increase in amount of antibody after vaccination, but the avidity of their serum antibodies tended to increase. Antibodies against denatured virus proteins varied with vaccine formulation; vaccines that are more recent have less total protein for the same amount of native hemagglutinin. We propose an index consisting of rank order of antibody level plus antibody avidity, both measured against native virus, plus hemagglutination-inhibition antibody titer, as a useful measure of immunity against influenza. [Copyright &y& Elsevier]

Objective Our studies aimed to measure the quality of antibody response to influenza vaccines in the elderly. The frequency of significant rise in hemagglutination inhibition (HAI) titer in the elderly is low and although annual vaccination reduces morbidity and mortality, better correlates of vaccine efficacy in the elderly are needed. Methods We measured the amount and avidity of serum antibodies against native H3N2 influenza glycoproteins or denatured virus (unfoldons) in pre- and post-vaccinated sera of 36 elderly subjects. Results Eighty percent of subjects had high pre-immunization antibody levels and only 13% showed ≥2fold increase after vaccination, but 33% showed ≥2fold increase in avidity. With increasing dosage there was a significant increase in avidity against unfoldons with 50% of subjects showing ≥2fold increase at the highest dose. Elderly subjects given subunit vaccine showed higher reactivity with unfoldons (78% of native) than younger subjects studied earlier who were given inactivated whole virus vaccine (19% of native). Conclusion The clear inverse relationship between pre-immunization antibody levels and antibody increase after vaccination implies that a major reason for the low frequency of antibody responses in elderly subjects is simply because they have high pre-immunization antibody levels. Only low reactivity was observed with earlier viruses. The increased proportion and avidity of antibodies against unfoldons is of concern, as these are not protective, and vaccine developers need to be aware of the role of age or vaccine formulation in inducing anti-unfoldon antibodies. [ABSTRACT FROM AUTHOR]

Abstract: There is still uncertainty on the correlates of protection by influenza vaccine. To determine the relationship between hemagglutination-inhibition (HI) titer and the specificity and avidity of serum antibodies, we analyzed serum from a longitudinal trial (1983–1987) of influenza vaccine efficacy [Keitel WA, Cate TR, Couch RB, Huggins LL, Hess KR. Efficacy of repeated annual immunization with inactivated influenza virus vaccines over a five year period. Vaccine 1997;15(10):1114–22 ]. We captured native virus particles with fetuin and separately measured relative antibody levels and avidities of antibodies against native glycoproteins and antibodies against denatured viral proteins. Most subjects had pre-existing antibodies against A/Victoria/75 and, although 70% had >two-fold increased antibodies against A/Philippines/82 after vaccination, only 30% showed increased antibodies to A/Victoria/75 indicating no dominance of original antigenic sin. There was variation in the levels of antibodies to unfolded antigens compared to native, but antibodies against denatured proteins never exceeded those against native virus. In some cases, the avidity increased without a significant increase in antibody concentration, which might explain why some vaccinees with low HI titer demonstrate adequate protection. We found that the negative correlation between pre-vaccination HI titer and the increase after vaccination is also seen when antibodies are measured directly, but that there is little relationship between HI titer and antibodies against native glycoproteins, either in amount or avidity. Our assay, which has also been adapted for recent influenza viruses that do not bind to fetuin, may be useful for vaccine evaluation. [Copyright &y& Elsevier]