Studies examine safety of adjuvanted pandemic vaccine

Jul 10, 2012 (CIDRAP News) – As researchers continue to sort out safety issues surrounding the monovalent vaccine used during the 2009 H1N1 flu pandemic, two new reports focusing mainly on an adjuvanted version suggest that immunization was safe for babies born to vaccinated pregnant women and that it was linked to a small but significant risk of Guillain-Barre syndrome (GBS) in some patients.

Both reports appear in the latest issue of the Journal of the American Medical Association (JAMA) and focus on an AS03-adjuvanted vaccine made by GlaxoSmithKline.

In the pregnancy study, Danish researchers studied a cohort of infants born in Denmark between Nov 2, 2009, and Sep 30, 2010. They obtained mothers' 2009 H1N1 vaccination status from a national database. The AS03-adjuvanted split virus vaccine was the only one used in Denmark.

Denmark's pandemic flu vaccination campaign launched on Nov 2, 2009, with pregnant women in the priority group. Pregnant women with underlying conditions were urged to get vaccinated during their first trimester, and those without such conditions were advised to receive it during the second or third trimester.

Using a cohort of 53,432 infants, researchers compared fetal outcomes among mothers who were and were not vaccinated. The main adverse outcomes they looked at were major birth defects, preterm birth, and smallness for gestational age.

Of the group, 6,989 babies were exposed to the vaccine during pregnancy, all but 345 of them in the second or third trimester.

The researchers found no association between vaccination during pregnancy and major birth defects, preterm birth, or fetal growth restriction.

The small number of babies exposed to the vaccine during the first trimester allowed the researchers to exclude only the larger risks, but even in that high-risk group, the results were reassuring, the authors said.

They wrote that while other studies have looked at fetal safety of H1N1 vaccination, theirs was the first to directly compare outcomes from vaccinated and unvaccinated mothers.

The results might be generalizable to nonadjuvanted vaccines because they contain identical viral antigens, though antigen doses and manufacturing processes may vary, the investigators wrote, adding that the results don't extend to vaccines that used other adjuvants.

The safety data on babies born to vaccinated mothers may have implications for future flu seasons and pandemics, especially when adjuvants are needed to achieve adequate immune response, the researchers said.

In the second study, researchers analyzed enhanced GBS surveillance that Quebec health officials ordered during the 2009 H1N1 vaccine campaign. The investigation was ordered by the province's chief medical officer under the Quebec Public Health Act. Quebec's pandemic flu vaccine campaign launched on Oct 26, 2009, targeting everyone age 6 months and older. About 96% of vaccinated Quebec residents received the AS03-adjuvanted vaccine, and vaccination status was verified with provincial registries.

The population-based cohort study followed patients over a 6-month period from October 2009 through March 2010. Physicians were urged to report suspected and confirmed GBS cases. Patients' records were reviewed by a physician, with assistance from adult and pediatric neurologists. Reviewers were blinded to the immunization status of the cases.

Over the study period, researchers identified 83 confirmed GBS cases, including 25 patients who had been vaccinated 8 or fewer weeks before symptom onset, most (19 of 25) of whom were vaccinated 4 or fewer weeks before GBS onset.

For those with GBS onset 8 or fewer weeks after vaccination, the relative risk was 1.80 (95% confidence interval, 1.2 to 2.87), and for those with the earlier onset the risk was 2.75 (95% CI, 1.63 to 4.62).

Overall, the team found that the number of GBS cases linked to vaccination was about 2 per 1 million doses. They observed a cluster of cases shortly after the vaccine campaign started, which they said wasn't likely to have been caused by flu infection. The group found no excess risk in people younger than 50.

For comparison, a US study of GBS in recipients of the unadjuvanted 2009 H1N1 vaccine found that there were about 0.8 excess cases of GBS per 1 million vaccinations, which is similar to that for the seasonal flu vaccine. A similar study in five European countries that used an adjuvanted vaccine found that vaccination probably didn't increase the GBS risk, but investigators couldn't rule out a slightly greater chance of suffering from the condition.

The Quebec researchers concluded that the adjuvanted 2009 H1N1 vaccine was linked to a small but significant GBS risk, but they said the benefits of immunization probably outweighed the risks.

In an accompanying JAMA editorial that addressed both of the studies, two infectious disease experts said it's important to assess the potential pandemic vaccine risks to fetuses as well as adults. The authors are Mark Steinhoff, MD, director of the Global Health Center at Cincinnati Children's Hospital Medical Center, and Noni MacDonald, MD, MSc, professor of pediatrics and computer sciences at Dalhousie University in Halifax, Nova Scotia.

"Taken together, these studies partially assuage concerns about the safety of adjuvanted pandemic influenza vaccines during pregnancy," they wrote. "However, more studies are needed examining other types of vaccine adjuvants."

They noted that observational studies of vaccines can be limited by biases and confounding by indication, adding that future studies with improved statistical design are needed to confirm the findings, such as prospective follow-up studies using virologic end points with adjustments for selection, seasonality, and other biases.

Pasternak B, Svanstrom H, Molgaard-Nielsen D, et al. Risk of adverse fetal outcomes following administration of a pandemic influenza A (H1N1) vaccine during pregnancy. JAMA 2012 Jul 11;308(2):165-74 [Abstract]

DeWals P, Deceunick G, Toth E, et al. Rick of Guillain-Barre syndrome following H1N1 influenza in Quebec. JAMA 2012 Jul 11;308(2):175-81[Abstract]

Steinhoff MC, MacDonald NE. Influenza pandemics—pregnancy, pathogenesis, and perinatal outcomes, editorial. JAMA 2012 Jul 11;308(2):184-85[Extract]

See also:

Jun 2, 2010, CIDRAP News story "CDC: GBS risk similar for H1N1 and seasonal flu vaccines"

Jul 13, 2011, CIDRAP News story "Study: adjuvanted H1N1 vaccines had little effect on GBS risk"

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