Increasing Doses of an Inactivated Influenza A/H1N1 Vaccine Induce Increasing Levels of Cross-Reacting Antibody to Subsequent, Antigenically Different, Variants
- 1 Department of Molecular Virology and Microbiology , Baylor College of Medicine, Houston, Texas
- 2 Department of Medicine; Baylor College of Medicine, Houston, Texas
- Reprints or correspondence: Dr. Wendy A. Keitel, Molecular Virology and Microbiology and Medicine, Baylor College of Medicine 280, One Baylor Plaza, Houston, TX 77030 (wkeitel{at}bcm.tmc.edu).
Abstract
Immunization approaches that will broaden antibody responses to antigenically different variants of influenza viruses are needed because vaccine strains do not always match the viruses that circulate during the subsequent epidemic. Sera collected from subjects who were vaccinated with various doses of influenza A/Taiwan/86 vaccine were assayed for the levels of antibody against 3 subsequent, antigenically different, A/H1N1 variants. Dose-related increases in antibody responses to all 4 viruses were observed, even against a virus appearing >10 years after vaccination. Increasing the influenza vaccine dosage safely and predictably enhanced antibody responses to the vaccine virus and to subsequent, antigenically different, influenza A/H1N1 variants.
Annual influenza epidemics are associated with excess deaths and hospitalizations, particularly among the elderly and persons with underlying diseases of the heart and lung [1, 2]. Trivalent inactivated vaccines (TIV) are recommended for the elderly and other persons who are at increased risk from complications following influenza; for persons who may transmit influenza to those who are at increased risk; and for persons who wish to reduce their risk of becoming infected [3]. Immune responses among elderly and other high-risk subjects after immunization with TIV are generally lower than those among younger, healthy persons, and efforts are underway to optimize vaccines for these populations [4].
Worldwide surveillance of circulating influenza viruses provides data used to select candidate viruses for the annually updated vaccines. Protection conferred by means of vaccination with TIV is greatest when the circulating viruses closely match the viruses used to prepare the vaccine [5]. However, the strains selected for inclusion in the vaccine do not always match the viruses that circulate in the subsequent influenza epidemic. Therefore, approaches that will broaden the immune responses, to provide protection against antigenically related but different viruses (i.e., drifted variants), are needed. Such approaches will have relevance for both interpandemic and pandemic influenza-vaccine development. One approach is to increase the dose of vaccine. Higher-than-usual dosages of TIV, purified influenza-virus hemagglutinin (HA), and recombinant HA are safe and elicit higher antibody responses to the vaccine viruses (6–11). In the present report, we show that higher doses also elicit higher antibody responses to subsequent, antigenically different, variants. Because the level of serum antibody is correlated with protection [12], higher vaccine dosages should improve protection against influenza.
Methods and results. We previously demonstrated that high dosages of a purified influenza-virus HA vaccine significantly enhanced serum and nasal secretion antibody responses in healthy young adults [8]. Written informed consent was obtained from potential subjects prior to screening, and the study was conducted in accordance with protocols approved by the local Institutional Review Boards. Subjects were assigned randomly to receive 1 of 5 doses (either 0 15, 45, 135, or 405 µg) of monovalent influenza A/Taiwan/1/86 (H1N1) HA. Dose-related increases in antibody responses to the vaccine virus were observed. Serum samples collected from these subjects were assayed later to determine both the level of hemagglutination inhibition (HAI) antibody against 3 subsequent, antigenically related but different, influenza A/H1N1 variants—A/Texas/91, A/Beijing/95, and A/New Caledonia/99—and the level of neutralizing antibody against A/New Caledonia/99, as described elsewhere [8].
The percentages of subjects who had significant increases in HAI-antibody levels after vaccination, the percentages of subjects who had putative protective titers of HAI antibody (⩾32), and the geometric mean titers (GMTs) of serum antibody against the vaccine strain and the 3 subsequent antigenic variants, both before and 4 weeks after vaccination, are shown in table 1. The responses to A/Taiwan were almost identical to those detected in the original assay. The serum antibody responses to the vaccine virus increased with higher doses; for each dose, 97%-100% of subjects achieved a titer of ⩾32 against the vaccine virus (A/Taiwan). For each of the 3 subsequent antigenic variants as well, the mean antibody titer increased significantly with higher doses. Compared with what was observed for subjects who were given the standard 15-µg HA dose, the percentage of subjects given higher doses who achieved the putative protective titer of ⩾32 was 15%–20% greater for the A/Texas variant, 20%-33% greater for the A/Beijing variant, and 7%-15% greater for the A/New Caledonia variant. In addition, the percentage of subjects who exhibited a significant antibody response in the neutralizing-antibody test with A/New Caledonia was 24%-34% greater than the percentage of subjects who received the standard 15-µg HA dose. Although immune responses to the vaccine antigen and the closely related A/Texas antigen appeared to level out at the 45-µg dose, statistically significant dose-related increases in responses to the subsequent antigenic variants (i.e., A/Beijing and A/New Caledonia) are clear over the entire dose range.
Table 1
Serum antibody responses before and after vaccination with increasing doses of an inactivated A/Taiwan (H1N1) hemagglutinin (HA) vaccine: responses to the vaccine antigen and to 3 subsequent, antigenically different variants.
Discussion. In the present study of healthy young adults, vaccination with increasing doses of a purified influenza HA vaccine induced increasing serum antibody responses not only to the vaccine virus, A/Taiwan/86 (H1N1), but also to 3 subsequent, antigenically related but different, A/H1N1 viruses. The period of time represented by the 4 variants was 13 years and spanned a period of selection of new A/H1N1 strains for incorporation into 4 different vaccines.
Active worldwide influenza surveillance provides data that are used to select virus seeds for production of vaccines aimed at control of interpandemic influenza each year. Because vaccine strains must be selected before the actual epidemic virus is known, antigenic mismatch may occur. Similar considerations pertain to the development of candidate pandemic vaccines. For example, newer influenza A/H5N1 viruses continue to represent antigenic drift [13], such that prepandemic vaccine viruses may not closely match the actual pandemic virus. In view of the fact that the level of protection against influenza is correlated with levels of serum antibody against the virus that causes the epidemic, vaccine approaches that elicit antibody responses to potential new variants are desirable. Increasing the dose of HA safely and predictably enhances the serum antibody response to the vaccine virus as well as to antigenically related but different variants. Although a titer of 32–40 after vaccination is a benchmark used to assess vaccine immunogenicity and is sometimes referred to as a protective level, no absolute level of antibody is protective, and the likelihood of protection increases with increasing levels of antibody [14]. The enhanced responses to drifted variants are most likely the result of increased levels of cross-reactive antibodies, and, in the present study, the ratio of antibody to A/Taiwan and drifted variants was similar regardless of dose.
The present study supports ongoing efforts to improve the immunogenicity of inactivated influenza virus vaccines for control of interpandemic influenza. Vaccines containing higher doses of influenza virus HA, including inactivated and recombinant influenza vaccines, have the potential to enhance protection, particularly among the elderly, whose immune responses after vaccination tend to be diminished and who are at increased risk for complications and death following influenza (9–11). Alternative approaches for enhancing serum antibody responses to vaccines include the use of adjuvanted formulations. In several studies, the adjuvant approach has been shown to enhance responses to both the vaccine viruses and related variants of potential pandemic viruses [15, 16]. Vaccination approaches that regularly ensure optimal serum antibody responses to the vaccine virus and to subsequent, antigenically different, variants should be developed for their ability to enhance protection against influenza.
Footnotes
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Potential conflicts of interest: W.A.K. has received research support from Protein Sciences, Inc., and research support from Novartis and GlaxoSmithKline is pending. R.B.C. has served as a consultant to GlaxoSmithKline and Dynavax.
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Financial support: National Institute of Allergy and Infectious Diseases (Division of Microbiology and Infectious Diseases contract N-01-AI-30039 to R.B.C.).
- Received February 20, 2008.
- Accepted April 10, 2008.
- © 2008 by the Infectious Diseases Society of America
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