In a prior study in the elderly, concentrations of the sp 2001–2002 influenza vaccine with increasing dosages (15 to 60 µg of each HA) induced an increase in serum antibody as dosage increased [16
]. This finding provoked sanofi pasteur to develop a new trivalent vaccine containing 60 µg of the HA of each virus strain but lacking gelatin and thimerosal, standard ingredients of past vaccines, for potential market development. To verify potential value, the 2004–2005 formulation of this vaccine was compared in this study to their licensed standard dosage vaccine. Subjects were stratified for receipt of standard vaccine the previous season before being randomized to receive high or standard dosage vaccine; 78% of subjects had received vaccine two to five months earlier. Serum antibody responses to the high dosage vaccine were significantly greater than those for the standard dosage for the total group of 414 subjects, those vaccinated and those not vaccinated the previous season, for antibody increase frequencies and magnitude of the increase for each of the three vaccine viruses (A/H1N1, A/H3N2, B) and in both HAI and neut tests. In addition, serum antibody responses to the high dosage vaccine were greater for the next succeeding antigenic variant of influenza A/H3N2 virus than were those for standard vaccine. While reaction reports after vaccinations were more common among those given the high dosage vaccine, the increased reactogenicity was mostly mild and well tolerated.
Increased dosages of viral antigens in inactivated influenza vaccines have induced increased serum antibody responses among humans in numerous vaccine trials in the past. Studies of dose response were performed using candidate “pandemic” influenza vaccines in 1957 (H2N2), 1968 (H3N2), 1976 (swine H1N1), and 1977 (Russian H1N1) [6
]. In addition, dose-response studies have been performed with a number of seasonal (interpandemic) vaccines [14
]. Dosages as high as 4800 CCA (chick cell agglutinating units) and 405 µg of HA have been shown to be well tolerated and to induce increased antibody responses as dosage is increased; increased dosage of the neuraminidase antigen also induced increased serum antibody responses to that antigen [7
]. The dose-response relationship for serum antibody responses in humans to increased dosage of inactivated influenza vaccine antigens is well established.
The serum HAI and neut antibody assays primarily measure anti-hemagglutinin (anti-HA) antibody and neutralization of influenza virus is mediated by antibody to the HA. Intramuscular administration of inactivated influenza vaccine induces this antibody in both serum and respiratory secretions and an inverse correlation between the resulting titer of anti-HA antibody and the frequency of infections and illnesses occurring in persons exposed to influenza viruses is also well established [5
]. Therefore, an increase in the antibody response from an increased vaccine dosage should lead to a reduction in infections and illnesses among exposed persons. In support of this expectation, comparisons of different dosages of type A vaccine in the past have demonstrated increased protection among persons given vaccine of increased dosage [9
A serum titer of ≥1:32 or 1:40 in HAI tests has been a useful marker for assessing frequencies of persons likely to be protected. Such a titer does not ensure protection, but as the titer increases, the likelihood of infection occurring is reduced. Although not always statistically significant, the proportions of subjects in the present study who achieved a titer of ≥1:32, ≥1:64, ≥1:128 in HAI tests were consistently greater after high dosage than after standard dosage for all analysis groups and all three vaccine viruses.
A concern for increasing the dosage in influenza vaccines is for an accompanying increase in reactogenicity. Local pain after vaccination was more common in the present study among those given the high dosage vaccine although the vaccine was well tolerated. Reactogenicity after influenza vaccine was common and sometimes severe prior to 1968 when purified vaccines were introduced [23
]. Refinements in vaccine manufacturing have led to vaccines that have low reactogenicity. However, increasing dosage has generally led to an increase in reactogenicity, usually for local pain and tenderness; other reactions, including systemic symptoms, may not be increased [12
In summary, the new high dosage influenza vaccine evaluated in this study was well tolerated by elderly subjects and induced significantly greater serum antibody responses than licensed standard dosage vaccine. Available information indicates that the increased immune response can be expected to increase the protection afforded. This is a desirable result since influenza continues to be a major medical problem, particularly among the elderly.