H1N1 Update: Early Results on Vaccine Indicate One Dose May Be Sufficient for Most Groups

H1N1 Update: Early Results on Vaccine Indicate One Dose May Be Sufficient for Most Groups

Preliminary studies of two vaccines against 2009 H1N1 virus reported online in the New England Journal of Medicine are "reassuring."

Using a variety of dosages and schedules, the industry-supported studies, done in Australia and the U.K., comprised some 300 healthy adults and evaluated the immunogenicity of the vaccines 3 weeks after administration. (One vaccine, derived from viruses grown in cell culture and not hens' eggs, contained adjuvant, which is not expected to be licensed for use in the U.S. this year.)

The immune response to a single 15-μg dose of unadjuvanted vaccine was rated as "robust" by researchers. Both vaccines showed good immunogenicity. The journal's editorialist says the data suggest that the single 15-μg dose "should be immunogenic" in the groups prioritized for vaccination; however, younger children will probably still require two shots. Side effects included tenderness at the injection site and pain.

The editorialist observes: "It is reassuring that the manufacturing process for these vaccines is identical to that used for seasonal vaccines, which have a strong record of safety."

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Response after One Dose of a Monovalent Influenza A (H1N1) 2009 Vaccine — Preliminary Report
Michael E. Greenberg, M.D., M.P.H., Michael H. Lai, B.Med.Sc., M.B., B.S., M.Med.Sc., Gunter F. Hartel, M.S., Ph.D., Christine H. Wichems, Ph.D., Charmaine Gittleson, B.Sc., M.B., B.Ch., Jillian Bennet, M.Sc., M.P.H., Gail Dawson, B.Pharm., Wilson Hu, M.D., M.B.A., Connie Leggio, B.Sc., Diane Washington, M.D., and Russell L. Basser, M.B., B.S., M.D., F.R.A.C.P. From Clinical Research and Development, CSL, Parkville, VIC, Australia. 

This article (10.1056/NEJMoa0907413) was published on September 10, 2009, at
NEJM.org. N Engl J Med 2009;361.Copyright © 2009 Massachusetts Medical Society.

Abstract
Background
A novel influenza A (H1N1) 2009 virus is responsible for the first influenza pandemic in 41 years. A safe and effective vaccine is urgently needed. A randomized, observer-blind, parallel-group trial evaluating two doses of an inactivated, splitvirus 2009 H1N1 vaccine in healthy adults between the ages of 18 and 64 years is ongoing at a single site in Australia.

Methods
This preliminary report evaluates the immunogenicity and safety of the vaccine 21 days after the first of two scheduled doses. A total of 240 subjects, equally divided into two age groups (<50 years and ≥50 years), were enrolled and underwent randomization to receive either 15 μg or 30 μg of hemagglutinin antigen by intramuscular injection. We measured antibody titers using hemagglutination-inhibition and microneutralization assays at baseline and 21 days after vaccination. The coprimary immunogenicity end points were the proportion of subjects with antibody titers of 1:40 or more on hemagglutination-inhibition assay, the proportion of subjects with either seroconversion or a significant increase in antibody titer, and the factor increase in the geometric mean titer.

Results
By day 21 after vaccination, antibody titers of 1:40 or more were observed in 116 of 120 subjects (96.7%) who received the 15-μg dose and in 112 of 120 subjects (93.3%) who received the 30-μg dose. No deaths, serious adverse events, or adverse events of special interest were reported. Local discomfort (e.g., injection-site tenderness or pain) was reported by 46.3% of subjects, and systemic symptoms (e.g., headache) by 45.0% of subjects. Nearly all events were mild to moderate in intensity.

Conclusions
A single 15-μg dose of 2009 H1N1 vaccine was immunogenic in adults, with mild-to-moderate vaccine-associated reactions. (ClinicalTrials.gov number, NCT00938639.)
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Trial of Influenza A (H1N1) 2009 Monovalent MF59-Adjuvanted Vaccine — Preliminary Report
Tristan W. Clark, M.R.C.P., Manish Pareek, M.R.C.P., Katja Hoschler, Ph.D., Helen Dillon, M.R.C.P., Karl G. Nicholson, M.D., F.R.C.P., Nicola Groth, M.D., and Iain Stephenson, M.D., F.R.C.P.

This article (10.1056/NEJMoa0907650) was published on September 10, 2009, at NEJM.org. N Engl J Med 2009;361. Copyright © 2009 Massachusetts Medical Society.

ABSTRACT
Background
The 2009 pandemic influenza A (H1N1) virus has emerged to cause the first pandemic of the 21st century. Development of effective vaccines is a public health priority.

Methods
We conducted a single-center study, involving 175 adults, 18 to 50 years of age, to test the monovalent influenza A/California/2009 (H1N1) surface-antigen vaccine, in both MF59-adjuvanted and nonadjuvanted forms. Subjects were randomly assigned to receive two intramuscular injections of vaccine containing 7.5 μg of hemagglutinin on day 0 in each arm or one injection on day 0 and the other on day 7, 14, or 21; or two 3.75-μg doses of MF59-adjuvanted vaccine, or 7.5 or 15 μg of nonadjuvanted vaccine, administered 21 days apart. Antibody responses were measured by means of hemagglutination-inhibition assay and a microneutralization assay on days 0, 14, 21, and 42 after injection of the first dose.

Results

•  Results of an interim analysis of the responses to the 7.5-μg dose of MF59-adjuvanted vaccine by days 14 and 21 are presented (data from four of the seven groups studied, for a total of 100 subjects). 
• The most frequent local and systemic reactions were pain at the injection site and muscle aches, noted in 70% and 42% of subjects, respectively. 
• Two subjects reported fever, with a temperature of 38°C or higher, after the first dosing. Antibody titers, expressed as geometric means, were generally higher at day 14 among subjects who had received two 7.5-μg doses of the MF59-adjuvanted vaccine than among those who had received only one by this time point (P = 0.04 by the hemagglutination-inhibition assay and P<0.001 by the microneutralization assay). 
• By 21 days after vaccination with the first dose of 7.5 μg of MF59-adjuvanted vaccine, the rates of seroconversion, as measured with the use of a hemagglutination-inhibition assay and a microneutralization assay, were 76% and 92% of subjects, respectively, who had received only one dose to date (with the second dose scheduled for day 21) and 88 to 92% and 92 to 96% of subjects, respectively, who had already received both doses (P = 0.11 and P = 0.64, respectively).

Conclusions
In preliminary analyses, the monovalent influenza A (H1N1) 2009 MF59-adjuvanted vaccine generates antibody responses likely to be associated with protection within 14 days after a single dose is administered. (ClinicalTrials.gov number, NCT00943358.)

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Cross-Reactive Antibody Responses to the 2009 Pandemic H1N1 Influenza Virus
Kathy Hancock, Ph.D., Vic Veguilla, M.P.H., Xiuhua Lu, M.D., Weimin Zhong, Ph.D., Eboneé N. Butler, M.P.H., Hong Sun, M.D., Feng Liu, M.D., Ph.D., Libo Dong, M.D., Ph.D., Joshua R. DeVos, M.P.H., Paul M. Gargiullo, Ph.D., T. Lynnette Brammer, M.P.H., Nancy J. Cox, Ph.D., Terrence M. Tumpey, Ph.D., and Jacqueline M. Katz, Ph.D.
 
From the Influenza Division, National Center for Immunization and Respiratory Diseases
This article (10.1056/NEJMoa0906453) was published on September 10, 2009, at
NEJM.org. N Engl J Med 2009;361. Copyright © 2009 Massachusetts Medical Society.
 
Abstract
Background
A new pandemic influenza A (H1N1) virus has emerged, causing illness globally, primarily in younger age groups. To assess the level of preexisting immunity in humans and to evaluate seasonal vaccine strategies, we measured the antibody response to the pandemic virus resulting from previous influenza infection or vaccination in different age groups.
 
Methods
Using a microneutralization assay, we measured cross-reactive antibodies to pandemic H1N1 virus (2009 H1N1) in stored serum samples from persons who either donated blood or were vaccinated with recent seasonal or 1976 swine influenza vaccines.
 
Results
A total of 4 of 107 persons (4%) who were born after 1980 had preexisting crossreactive
antibody titers of 40 or more against 2009 H1N1, whereas 39 of 115 persons (34%) born before 1950 had titers of 80 or more. Vaccination with seasonal trivalent inactivated influenza vaccines resulted in an increase in the level of crossreactive antibody to 2009 H1N1 by a factor of four or more in none of 55 children between the ages of 6 months and 9 years, in 12 to 22% of 231 adults between the ages of 18 and 64 years, and in 5% or less of 113 adults 60 years of age or older. Seasonal vaccines that were formulated with adjuvant did not further enhance
cross-reactive antibody responses. Vaccination with the A/New Jersey/1976 swine influenza vaccine substantially boosted cross-reactive antibodies to 2009 H1N1 in adults.
 
Conclusions
Vaccination with recent seasonal nonadjuvanted or adjuvanted influenza vaccines induced little or no cross-reactive antibody response to 2009 H1N1 in any age group. Persons under the age of 30 years had little evidence of cross-reactive antibodies to the pandemic virus. However, a proportion of older adults had preexisting cross-reactive antibodies.

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