Elsevier

Vaccine

Volume 20, Issues 7–8, 15 January 2002, Pages 1099-1105
Vaccine

Evaluation of a single dose of half strength inactivated influenza vaccine in healthy adults

https://doi.org/10.1016/S0264-410X(01)00440-6Get rights and content

Abstract

Because of delays in the manufacturing of the 2000–2001, trivalent inactivated influenza vaccine in the US, there were concerns that there might be shortages of vaccine supply in the US. Therefore, we conducted a prospective, randomized, open-label, multicenter trial at six academic medical centers in the US, to evaluate the immunogenicity of a half dose of inactivated vaccine in healthy adults. Healthy adults between the ages of 18 and 49 were randomized to receive either a full 0.5 ml (15.5 μg of each HA antigen) dose or a 0.25 ml (7.75 μg of each HA antigen) dose of the 2000–2001 trivalent inactivated influenza vaccine by intramuscular injection. Sera were obtained for assessment of hemagglutination-inhibiting antibody to each of the three strains contained in the vaccine before and 21 days after vaccination. The proportions of individuals achieving a post-vaccination titer of ≥1:40, the geometric mean titers (GMTs) of post-vaccination antibody, and the proportions of individuals with a four-fold or greater increase in antibody were lower for all three strains in those receiving 0.25 ml of vaccine compared to those receiving 0.5 ml. However, the differences were small for all three antigens. The upper 95% confidence limits for differences between 0.25 and 0.5 ml doses were less than 20% for rates of achieving a titer of ≥1:40 and four-fold response, and less than 1.5 for the ratios of GMTs between dose groups, for all three vaccine antigens. These results suggest that when vaccine is in short supply, a strategy using a half dose in healthy adults could increase the number of people vaccinated with relatively little adverse impact on vaccine immunogenicity.

Introduction

The most effective tool currently available for control of influenza is annual administration of inactivated influenza vaccine. Vaccination is particularly recommended for use in individuals at high-risk for influenza-related complications [1], but it is also recommended for healthy adults in a variety of situations. It is estimated that approximately 50 million doses of vaccine were administered, to high-risk adults in the US in 1999–2000, and that at least 70 million doses would be needed to vaccinate all high-risk individuals in the US.

Delays in production of the 2000–2001 inactivated influenza vaccine in the US caused significant concern that the number of available doses would not be sufficient to support vaccine use at the desired level. Eventually, sufficient quantities of vaccine were produced to meet demand. However, contingency planning is needed for similar situations in the future because the yield of influenza viruses in vaccine production varies with the strain and is not entirely predictable.

One strategy to increase the number of persons who could be immunized, in a situation of critical shortage of vaccine would be to administer a lower dose of vaccine to some groups. Currently, trivalent inactivated influenza vaccines are given intramuscularly to adults as a 0.5 ml dose that is standardized to contain at least 15 μg of each hemagglutinin as measured by single radial immunodiffusion (SRID) [2]. The relatively few studies available regarding the immunogenicity, of lower doses of modern influenza vaccines suggest that doses of 5–10 μg of hemagglutinin are only slightly less immunogenic than are doses of 15–20 μg in adults, who have been primed by previous infection or vaccination [3], [4], [5], [6].

We conducted the current study, in order to obtain more information on the safety and immunogenicity of lower dose influenza vaccine. Since the most likely group in whom a low dose strategy would be implemented would be individuals who normally respond well to vaccination, the focus of this evaluation was on healthy young adults. The primary outcome measure was the development of hemagglutination-inhibiting antibody, a simple measure of functional antibody that correlates with protection [7].

Section snippets

Study design

The study was conducted as a prospective, multicenter, randomized, open-label trial. Eligible participants were stratified into two groups based on self-reported history of previous receipt of inactivated influenza vaccine within the past 3 years, individuals reporting vaccination within the last 3 years and those reporting no such vaccination. Subjects within each group were randomized to receive a single dose of either 0.5 or 0.25 ml of trivalent inactivated influenza vaccine by intramuscular

Results

A total of 1009 subjects were enrolled in this study during the 2-week-period between 9 and 23 August 2000, including 569 subjects who reported vaccination in the last 3 years and 440 subjects who did not. Among previously vaccinated subjects, 283 were randomized to the half dose group and 286 to full dose. Among those who had not been vaccinated previously, 220 subjects were randomized to the half dose and 220 to the full dose. Three subjects, all in the half dose group, did not complete the

Discussion

Several trials evaluating the dose-dependent immune response to inactivated influenza vaccines were conducted in the years immediately following the emergence of H1N1 influenza viruses in the late 1970s. These trials, which also utilized whose HA content was quantified by SRID, generally showed an increased frequency and magnitude of responses at higher (∼20 μg HA) than lower (∼7 μg HA) doses of HA antigen [3], [4], [5], [6]. However, these differences were small and not seen in all studies.

Acknowledgements

The authors would like to thank Nancy Cox, Joel Ward, Robert Edelman, Mark Van Raden and Bill Blackwelder for critical advice in study design and review of the manuscript, and acknowledge the efforts of the following individuals in the conduct of the study: Inger Baker, JoAnna Becker, Renee Bellrichard, Nanette Bond, Pat Chatfield, Jeanne Comstock, Carol Farnworth, Jocelyn Guevarra, Henrietta Hall, Amy Hoeper, Patricia Koops, Tracey Liddell, Stephen Lindstrom, Teresa Liu, James Love, Jonathan

References (15)

There are more references available in the full text version of this article.

Cited by (61)

  • Memory B Cell Activation, Broad Anti-influenza Antibodies, and Bystander Activation Revealed by Single-Cell Transcriptomics

    2020, Cell Reports
    Citation Excerpt :

    However, the transcriptional programs of these expanded clones and the antigen specificity of their antibodies have not been characterized. Analogously, antigen-resolved measurements, such as serum binding assays and antigen-specific cell sorting, have demonstrated that antigen-specific serum antibody (Belshe et al., 2004; Treanor et al., 2002), memory B cells (Crotty et al., 2004), and antibody-secreting cells (Wrammert et al., 2008) become more abundant after vaccination. However, these approaches have not been able to resolve clonal relationships among antigen-specific cells, the population dynamics of these clones, or their gene expression programs.

  • Immunization in cancer patients: Where we stand

    2015, Pharmacological Research
    Citation Excerpt :

    By anticipation of vaccine shortage during epidemics, randomized studies have been run in healthy individuals, especially with influenza vaccine [50–52], and PPV23 [37], to compare the efficacy and safety of half-dose – and even lower doses – to the conventional dose of vaccine antigen. In healthy individuals, the immune response to a half-dose of influenza was either non-inferior [50,51], or eventually slightly decreased [52] when compared to a full dose, both in terms of seroprotection, and of GMTs. Similar findings were published for HBV vaccine in young healthy adults [53], and for meningococcal serogroup B vaccine in healthy infants [54].

  • Acute exercise enhancement of pneumococcal vaccination response: A randomised controlled trial of weaker and stronger immune response

    2012, Vaccine
    Citation Excerpt :

    Direct comparison of responses in the resting control groups between full and half dose recipients only revealed small differences (significant in only 1 strain, although all strains showed smaller responses in the half dose group). These findings are not entirely unexpected given previous work aimed at examining dose-sparing procedures find similarly little to no inferiority in response in healthy adults receiving half-dose vaccines [33,35,36], and further suggests the importance of examining the effects of acute exercise as an adjuvant in populations with known sub-optimal responses. The finding that exercise effects were only significant in the half-dose group when control responses were similar is likely due to greater individual variation in the generally less robust response.

View all citing articles on Scopus
View full text