[MarinTeams] Response after One Dose of a Monovalent Influenza A (H1N1) 2009 Vaccine — Preliminary Report - NEJM

Fri Sep 11 11:24:45 EDT 2009

DC3, et al.
These just came out late yesterday.
John

John Buffum, PharmD, BCPP
Clinical Professor of Pharmacy, UCSF
Vice President, Marin County Pharmaceutical Association

Published at www.nejm.org September 10, 2009 (10.1056/NEJMoa0907413)

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.

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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, split-virus 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 [http://content.nejm.org/math/ge.gif] 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 [ClinicalTrials.gov]<http://content.nejm.org/cgi/external_ref?access_num=NCT00938639&link_type=CLINTRIALGOV> .)

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Published at www.nejm.org September 10, 2009 (10.1056/NEJMe0908224)

Pandemic Influenza Vaccine Policy — Considering the Early Evidence
Kathleen M. Neuzil, M.D., M.P.H.

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"Policy decisions regarding influenza rest on judgments about the behavior of the virus, the impact of the disease and our ability to interdict its course. But the virus is capricious, the disease elusive, and our remedies imperfect," said a report on the 1976 swine-flu epidemic at Fort Dix.1<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R1>

Two peer-reviewed articles now publicly available at NEJM.org, by Greenberg et al. (ClinicalTrials.gov number, NCT00938639 [ClinicalTrials.gov]<http://content.nejm.org/cgi/external_ref?access_num=NCT00938639&link_type=CLINTRIALGOV> )2<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R2> and Clark et al. (NCT00943358 [ClinicalTrials.gov]<http://content.nejm.org/cgi/external_ref?access_num=NCT00943358&link_type=CLINTRIALGOV> ),3<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R3> describe preliminary data on the immunogenicity of the influenza A (H1N1) 2009 monovalent vaccine. These data have been eagerly anticipated, as governments, public health officials, and other stakeholders respond to the first influenza pandemic in over 40 years. The authors and their collaborators are to be commended for their prompt execution of the trials and rapid sharing of the results.

The study by Greenberg et al. shows that a single dose of nonadjuvanted vaccine containing the usual 15 µg of hemagglutinin (HA) antigen is immunogenic in a high proportion of healthy young and middle-aged adults.2<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R2> These findings are welcome and reassuring, as there is little evidence of cross-reactive antibody against the novel 2009 pandemic influenza A (H1N1) virus in the general population, and the need for two doses had been predicted. Without a nonimmunized control group, it is impossible to determine whether subclinical infection may have boosted the immune response elicited by the vaccine. The study was conducted in Australia during a time when the pandemic virus was circulating, and one participant had laboratory-confirmed infection with the 2009 H1N1 virus during the course of the study. Therefore, responses could be somewhat lower if vaccine is administered under different epidemiologic circumstances.

In the study by Clark et al., one or two doses of an adjuvanted influenza vaccine containing 7.5 µg of HA (50% of the standard dose), administered on various schedules, elicited robust antibody titers.3<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R3> Although two doses (for a total of 15 µg of HA) yielded higher antibody levels than one dose, the seroprotective titer was attained in at least 80% of subjects in every group. Without a nonadjuvanted control group, it is impossible to determine the contribution of the adjuvant to these responses. Two previous studies comparing half-dose to full-dose seasonal vaccines support the finding that nonadjuvanted influenza vaccine may be immunogenic at a dose of 7.5 µg.4<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R4>,5<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R5> Pending data from the nonadjuvanted group studied by Clark et al. are vital to understanding the contribution of adjuvant to the immunogenicity of this vaccine.

Antibody levels as measured by both the hemagglutination-inhibition assay and the microneutralization assay correlate with protection against clinical illness from influenza infection. However, for any individual strain, it is not possible to determine a threshold above which protection can be ensured. The robustness and consistency of the antibody responses, and the use of internationally standardized reagents and controls, are reassuring and lend credibility to the results of Greenberg et al. and Clark et al.

The obvious advantage of a one-dose schedule is that, in the current time of vaccine scarcity, it doubles the number of people who may be vaccinated with a fixed amount of vaccine. Another clear advantage to the one-dose schedule is that antibody responses develop sooner. In the present situation of widespread circulation of the 2009 H1N1 virus occurring in many areas of the world, achieving protection 3 to 4 weeks earlier with one dose, rather than later on a two-dose schedule, is advantageous. From a logistic standpoint, administering one dose will greatly simplify vaccination programs and should reduce costs.

These immunogenicity data are difficult to extrapolate to children or to adults who have underlying immune suppression or high-risk conditions, for whom influenza vaccine is recommended. Experience with traditional seasonal vaccines tells us that the immune responses in older children, pregnant women, and immunocompetent adults with chronic conditions are roughly similar to those of healthy nonpregnant adults.6<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R6>,7<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R7> On this basis, the new data suggest that the standard 15-µg HA dose of the 2009 H1N1 vaccine should be immunogenic in those groups. The immune responses in children are unknown. Owing to the recognized morbidity associated with the 2009 H1N1 virus in children, this population is recommended to be among the first to receive vaccine in the United States.8<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R8>,9<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R9> Younger children generally have inferior responses to inactivated vaccines, as compared with healthy adults, and children under 9 years of age are recommended to receive two doses the first year that they receive influenza vaccine.9<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R9> Immunogenicity data in young children are critical to guide policy decisions.

In our current global situation, in which demand for influenza vaccine greatly exceeds supply, dose-sparing strategies are needed.10<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R10> Fewer or partial doses and the use of adjuvants can all contribute to increased global vaccine supply. The studies by Greenberg et al. and Clark et al. provide evidence that such strategies may be successful for the current pandemic. On the basis of these data, it would be appropriate to begin vaccination with the use of one dose of the usual antigen content. In children, two doses may be needed, but vaccine should not be held in reserve to be used for a second dose.9<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R9> Although the adjuvanted vaccines are not licensed and not expected to be licensed for the coming season in the United States, they have been used in other countries, and their use could increase the number of persons who receive the benefit of vaccination. The adjuvant used by Clark et al., MF59, represents a class of oil-in-water adjuvants with demonstrated immunogenicity when combined with avian influenza strains that have HA-antigen contents as low as 3.75 µg. Immunogenicity data for the 3.75-µg dose of vaccine are pending, but positive results would allow supplies to be stretched even further.

Both vaccines tested have generally acceptable side-effect and adverse-event profiles, with pain or tenderness at the injection site being the most common adverse event observed. The local reactions seen with the adjuvanted vaccines were moderately higher than those generally seen with nonadjuvanted vaccines.7<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R7> Any association of uncommon adverse events with the vaccine cannot be ascertained in studies of this size. 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. Although concerns linger about the association of the 1976 swine influenza vaccine with the Guillain–Barré syndrome, the syndrome was rare, with approximately 1 case for every 100,000 persons vaccinated. The rate was even lower among persons under 25 years of age.11<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R11> One notable difference is that in 1976, we did not have a pandemic influenza virus that was spreading quickly throughout the world, and causing illness and death, as we do today. A plan for robust and comprehensive safety surveillance should be in place to detect uncommon events rapidly during the upcoming vaccination campaigns, so that risk–benefit ratios can be reassessed.

Additional studies are ongoing that will address the immunogenicity of live-attenuated vaccines, and additional inactivated vaccines, in various age groups and on various schedules and in combination with seasonal influenza vaccines. The desire to see all the available data must be balanced with the need to deploy vaccine quickly to reduce morbidity associated with the pandemic. Likewise, the need to make timely decisions must be balanced with thoughtful, transparent debate and openness to changing direction as new data emerge.1<http://content.nejm.org/cgi/content/full/NEJMe0908224?query=TOC#R1>

No potential conflict of interest relevant to this article was reported.

Source Information

>From PATH, Seattle.

This article (10.1056/NEJMe0908224) was published on September 10, 2009, at NEJM.org.

References

 1.  Neustadt RE, Fineberg HV. The swine flu affair: decision-making on a slippery disease. (Accessed September 9, 2009, at http://www.iom.edu/?id=65926.)
 2.  Greenberg ME, Lai MH, Hartel GF, et al. Response after one dose of a monovalent influenza A (H1N1) 2009 vaccine — preliminary report. N Engl J Med 2009;361. DOI: 10.1056/NEJMoa0907413.
 3.  Clark TW, Pareek M, Hoschler K, et al. Trial of influenza A (H1N1) 2009 monovalent MF59-adjuvanted vaccine — preliminary report. N Engl J Med 2009;361. DOI: 10.1056/NEJMoa0907650.
 4.  Treanor J, Keitel W, Belshe R, et al. Evaluation of a single dose of half strength inactivated influenza vaccine in healthy adults. Vaccine 2002;20:1099-1105. [CrossRef]<http://content.nejm.org/cgi/external_ref?access_num=10.1016%2FS0264-410X%2801%2900440-6&link_type=DOI>[Web of Science]<http://content.nejm.org/cgi/external_ref?access_num=000173858200016&link_type=ISI>[Medline]<http://content.nejm.org/cgi/external_ref?access_num=11803070&link_type=MED>
 5.  Engler RJ, Nelson MR, Klote MM, et al. Half- vs full-dose trivalent inactivated influenza vaccine (2004-2005): age, dose, and sex effects on immune responses. Arch Intern Med 2008;168:2405-2414. [Free Full Text]<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=archinte&resid=168/22/2405>
 6.  Sumaya CV, Gibbs RS. Immunization of pregnant women with influenza A/New Jersey/76 virus vaccine: reactogenicity and immunogenicity in mother and infant. J Infect Dis 1979;140:141-146. [Web of Science]<http://content.nejm.org/cgi/external_ref?access_num=A1979HM24000001&link_type=ISI>[Medline]<http://content.nejm.org/cgi/external_ref?access_num=479636&link_type=MED>
 7.  Fiore AE, Shay DK, Broder K, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep 2009;58:1-52. [Erratum, MMWR Recomm Rep 2009;58:896-7.] [Medline]<http://content.nejm.org/cgi/external_ref?access_num=19730409&link_type=MED>
 8.  Surveillance for pediatric deaths associated with 2009 pandemic influenza A (H1N1) virus infection -- United States, April-August 2009. MMWR Morb Mortal Wkly Rep 2009;58:941-947. [Medline]<http://content.nejm.org/cgi/external_ref?access_num=19730406&link_type=MED>
 9.  Use of influenza A (H1N1) 2009 monovalent vaccine -- recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep 2009;58:1-8. [Medline]<http://content.nejm.org/cgi/external_ref?access_num=19730409&link_type=MED>
 10. Yamada T. Poverty, wealth, and access to pandemic influenza vaccines. N Engl J Med 2009;361:1129-1131. [Free Full Text]<http://content.nejm.org/cgi/ijlink?linkType=FULL&journalCode=nejm&resid=NEJMp0906972v1>
 11. Hurwitz ES, Schonberger LB, Nelson DB, Holman RC. Guillain-Barré syndrome and the 1978-1979 influenza vaccine. N Engl J Med 1981;304:1557-1561. [Abstract]<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=304/26/1557>
 12.

Published at www.nejm.org September 10, 2009 (10.1056/NEJMoa0907650)

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.

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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 [ClinicalTrials.gov]<http://content.nejm.org/cgi/external_ref?access_num=NCT00943358&link_type=CLINTRIALGOV> .)

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