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Avoiding Guillan-Barre Syndrome Following Swine Origin Pandemic H1N1 2009 Influenza Vaccination - CORRESPONDENCE
The Journal of Infectious Diseases Nov 15 2009;200:1627-1628 Reprints or correspondence: Associate Professor Damon Eisen, Victorian Infectious Diseases Service, Royal Melbourne Hospital, Grattan St, Victoria, Australia, 3050 (
To the Editor-In learning from history, the infectious diseases community needs to be cognizant of the consequences of swine influenza vaccination. In 1976, a considerable number of patients in the United States died of H1N1/NJ/76 vaccine-induced Guillan-Barre Syndrome (GBS) [1]. We were pleased to read the recent article by Evans et al [2] that highlights this issue, and we wish to further explore the pathogenesis of this vaccine-related severe adverse effect. By doing so we wish to call on vaccine producers to concentrate their efforts on reassuring the medical community and therapeutic product regulators that current vaccines against pandemic H1N1 will be unlikely to induce GBS.
The similarities between the mild 1976 swine influenza season in the United States and the current pandemic H1N1 influenza are lessening with time. In the Southern Hemisphere, it is increasingly apparent that influenza in the 2009 influenza season is overwhelmingly due to pandemic H1N1 infection. Additionally, although it is predominantly a mild infection, it is causing increased morbidity among hospitalized patients, with a high prevalence of intensive care admission. For instance, at the Royal Melbourne Hospital, from 30 May 2009 through 16 July 2009, 5 of 27 hospitalized patients with proven pandemic H1N1 infection required mechanical ventilation in the intensive care unit. Therefore, the historical context of the H1N1/NJ/76 vaccine program that was halted when the risk of GBS apparently outweighed the benefit of protection from swine influenza is unlikely to be replicated. As indicated by Evans et al, the possible pathogenesis of GBS induced by H1N1/NJ/76 has been recently elucidated [3], and we believe that this must inform influenza vaccine manufacturers' strategies for prelicensure assessment of pandemic influenza vaccines.
The demonstration that the H1N1/NJ/76 vaccine, along with other seasonal influenza vaccines, induces anti-ganglioside protein GM1 antibodies in mice is a substantial observation [3]. Further, that the H1N1/NJ/76 vaccine hemagglutinin retained virally encoded sialic acid residues because of a relative lack of neuraminidase activity [4], increasing the molecular mimicry between the vaccine hemagglutinin and the monosialylated GM1, provides a biologically plausible if ultimately unproven explanation for the increase in GBS prevalence following H1N1/NJ/76 vaccination. The absence of human studies of anti-GM1 antibody induction by influenza vaccines does not disprove this hypothesis but suggests an important addition to prelicensure studies of current pandemic H1N1 vaccines. The proposed alternative etiology for the high rates of GBS following H1N1/NJ/76 vaccination is that there was increased intrinsic molecular mimicry between H1N1/NJ/76 hemagglutinin and GM1 [3]. There is a considerable evolutionary distance between H1N1/NJ/76 and a strain representative of the current pandemic, H1N1/California/09 (see dendrogram at
Aligning the swine-origin hemagglutinins from the 1976 and 2009 viruses (A/New Jersey/8/1976 [GenBank accession no CY039991] and A/California/7/2009 [GenBank accession no FJ969540]) at the nucleotide and deduced peptide sequence levels also shows that there has been considerable mutation in the hemagglutinin gene. There is an identity of 88.6% by nucleotide and 90.8% by amino acid sequence between these viruses. The extent of evolution of current pandemic H1N1 from H1N1/NJ/76 should hopefully reduce the likelihood that the current pandemic virus recapitulates the possible GM1 mimicry of the former swine-origin influenza, but the degree of epitope relatedness between the hemagglutinins of these viruses is unresolved.
Current recombinant subunit pandemic H1N1 hemagglutinin vaccines could evade the risk of increased GM1 mimicry if sialylation is controlled. These vaccines and the traditional egg-produced vaccines may both risk causing GBS if the pathogenesis is attributable to intrinsic mimicry between the present pandemic H1N1 and human GM1.
Evans et al [2] calculate that a prelicensure vaccine study would need to include 409,000-970,000 subjects to rule out an increased risk of GBS due to current pandemic H1N1 vaccines. Studies of this size are not feasible, and therefore, postlicensure studies will need to be relied on to assess the risk of GBS. It would be reassuring to know on biochemical and immunological grounds that the vaccine antigens to be used in vaccines for the current H1N1 pandemic have a low likelihood of causing GBS. Two approaches may help reassure medical staff and high-risk patients who will be the first to be vaccinated with vaccines for the pandemic. These are analyses of the sialylation status of vaccine hemagglutinin and of anti-GM1 antibody production in human vaccinees in prelicensure studies. The infectious diseases community must encourage influenza vaccine manufacturers to do everything possible to reduce the risk of history repeating itself if vaccines against the current swine flu-originated pandemic virus cause a potentially lethal neurological disease in trying to prevent a viral infection that overall remains relatively mild.
1.Haber P, Sejvar J, Mikaeloff Y, DeStefano F. Vaccines and Guillain-Barre syndrome. Drug Saf 2009;32:309-23.
2.Evans D, Cauchemez S, Hayden FG. "Prepandemic" immunization for novel influenza viruses, "swine flu" vaccine, Guillain-Barre syndrome, and the detection of rare severe adverse events. J Infect Dis 2009;200:321-8.
3.Nachamkin I, Shadomy SV, Moran AP, et al. Anti-ganglioside antibody induction by swine (A/NJ/1976/H1N1) and other influenza vaccines: insights into vaccine-associated Guillain-Barre syndrome. J Infect Dis 2008;198:226-33.
4.Kendal AP, Noble GR, Dowdle WR. Neuraminidase content of influenza vaccines and neuraminidase antibody responses after vaccination of immunologically primed and unprimed populations. J Infect Dis 1977;136(Suppl):S415-24.
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