[Unidentified]: In thinking about swine influenza, should we not be worried about GBS (Guillain-Barr? Syndrome)?
Dr. Dowdle: In 1976, there were field trials of the vaccine, but not to detect adverse events, just to look at immunologic response. That was not a major issue, and it was thought that the GBS risk was small compared with need for H1N1 vaccine.
Dr. Edwards: Are sera still available from the people who got GBS? Were they ever reevaluated?
Dr. Schonberger: No. There was one study after the outbreak that looked at possible HLA associations to see if any HLA type might be a risk factor. The study matched vaccinated GBS cases with vaccinated people without GBS and unvaccinated GBS cases with unvaccinated people without GBS to look for risk factors of GBS other than the receipt of the A/New Jersey/76 influenza vaccine. That study showed no clear association between GBS and HLA.
The comparison of case with control subject pairs for history of previous influenza vaccination, however, showed a statistically significant odds ratio of (0.23) suggesting protection against swine flu vaccine-related GBS if the recipient had a history of a previous influenza vaccination. With regard to leftover sera from this study, we have looked and can't find any.
Recently a study by Nachamkin and colleagues was published that involved the use of some saved swine flu vaccines that after thawing were used to inject into mice. Test results of the sera in these mice were then compared with test results of the sera in other mice injected with other seasonal influenza vaccines not associated with GBS. One key hypothesis suggested in a report of the Institute of Medicine (IOM) was that the swine flu vaccines might have been contaminated somehow with Campylobacter jejuni, a known trigger of GBS; Nachamkin's study showed that no antibodies against Campylobacter antigens were elicited in swine flu vaccine inoculated mice, indicating that this agent did not play a role in the swine flu vaccines' triggering of GBS.
However, each of the influenza vaccines (swine flu vaccines and the subsequent seasonal vaccines) led to production of anti-ganglioside antibodies (anti-GM1) in the inoculated mice. Unfortunately, the Nachamkin study did not quantify the levels of GM1 antibodies induced by the different vaccines. Anti-ganglioside antibodies have been shown in other studies to be associated in humans with GBS. In large part because the technique used in the Nachamkin study detected the presence, but not the amount, of anti-GM1 antibodies, there's still work to be done to determine whether these anti-GM1 antibodies are associated in the mouse model specifically with the 1976 swine flu vaccines that had a higher risk of triggering GBS.
The A/New Jersey/76 (H1N1) vaccine was unique among influenza vaccines in its relatively high risk of triggering GBS in 1976, and no one knows why. The same paper by Nachamkin and colleagues offered a speculative hypothesis, based on earlier work, that the 1976 vaccines' triggering of GBS may have been related to their low content of neuraminidase. This low level of neuraminidase in the 1976 swine flu vaccines was reported in the scientific literature by Dr. Alan Kendal, Ph.D. Unfortunately, we don't have published levels of neuraminidase for other influenza vaccines; neuraminidase levels are not routinely checked. Neuraminidase mediates the removal of sialic acid on hemagglutinin.
A low level of neuraminidase might have allowed for sufficient sialic acid to remain bound to hemagglutinin to mimic an epitope on nerves. Given this hypothesis, it may be reassuring that the new 2009 (H1N1) influenza virus has a substantially different neuraminidase than the A/New Jersey/76 (H1N1) virus, the former was derived from birds the latter from swine.
In addition, the hemagglutinin from the 2009 virus demonstrates antigenic drift differences from that present in the 1976 virus, although I learned today that the 1976 vaccine may provide some cross-protection against the new 2009 (H1N1) influenza virus, a potentially unexpected benefit from the 1976 swine flu vaccination campaign.
http://www.hhs.gov/aspr/conferences/nbsb/nbsb-h1n1forum-sum-090617.pdf
Dr. Dowdle: In 1976, there were field trials of the vaccine, but not to detect adverse events, just to look at immunologic response. That was not a major issue, and it was thought that the GBS risk was small compared with need for H1N1 vaccine.
Dr. Edwards: Are sera still available from the people who got GBS? Were they ever reevaluated?
Dr. Schonberger: No. There was one study after the outbreak that looked at possible HLA associations to see if any HLA type might be a risk factor. The study matched vaccinated GBS cases with vaccinated people without GBS and unvaccinated GBS cases with unvaccinated people without GBS to look for risk factors of GBS other than the receipt of the A/New Jersey/76 influenza vaccine. That study showed no clear association between GBS and HLA.
The comparison of case with control subject pairs for history of previous influenza vaccination, however, showed a statistically significant odds ratio of (0.23) suggesting protection against swine flu vaccine-related GBS if the recipient had a history of a previous influenza vaccination. With regard to leftover sera from this study, we have looked and can't find any.
Recently a study by Nachamkin and colleagues was published that involved the use of some saved swine flu vaccines that after thawing were used to inject into mice. Test results of the sera in these mice were then compared with test results of the sera in other mice injected with other seasonal influenza vaccines not associated with GBS. One key hypothesis suggested in a report of the Institute of Medicine (IOM) was that the swine flu vaccines might have been contaminated somehow with Campylobacter jejuni, a known trigger of GBS; Nachamkin's study showed that no antibodies against Campylobacter antigens were elicited in swine flu vaccine inoculated mice, indicating that this agent did not play a role in the swine flu vaccines' triggering of GBS.
However, each of the influenza vaccines (swine flu vaccines and the subsequent seasonal vaccines) led to production of anti-ganglioside antibodies (anti-GM1) in the inoculated mice. Unfortunately, the Nachamkin study did not quantify the levels of GM1 antibodies induced by the different vaccines. Anti-ganglioside antibodies have been shown in other studies to be associated in humans with GBS. In large part because the technique used in the Nachamkin study detected the presence, but not the amount, of anti-GM1 antibodies, there's still work to be done to determine whether these anti-GM1 antibodies are associated in the mouse model specifically with the 1976 swine flu vaccines that had a higher risk of triggering GBS.
The A/New Jersey/76 (H1N1) vaccine was unique among influenza vaccines in its relatively high risk of triggering GBS in 1976, and no one knows why. The same paper by Nachamkin and colleagues offered a speculative hypothesis, based on earlier work, that the 1976 vaccines' triggering of GBS may have been related to their low content of neuraminidase. This low level of neuraminidase in the 1976 swine flu vaccines was reported in the scientific literature by Dr. Alan Kendal, Ph.D. Unfortunately, we don't have published levels of neuraminidase for other influenza vaccines; neuraminidase levels are not routinely checked. Neuraminidase mediates the removal of sialic acid on hemagglutinin.
A low level of neuraminidase might have allowed for sufficient sialic acid to remain bound to hemagglutinin to mimic an epitope on nerves. Given this hypothesis, it may be reassuring that the new 2009 (H1N1) influenza virus has a substantially different neuraminidase than the A/New Jersey/76 (H1N1) virus, the former was derived from birds the latter from swine.
In addition, the hemagglutinin from the 2009 virus demonstrates antigenic drift differences from that present in the 1976 virus, although I learned today that the 1976 vaccine may provide some cross-protection against the new 2009 (H1N1) influenza virus, a potentially unexpected benefit from the 1976 swine flu vaccination campaign.
http://www.hhs.gov/aspr/conferences/nbsb/nbsb-h1n1forum-sum-090617.pdf
