By Anne Louise Bischoff
Chairman: Kjeld Schmiegelow
Opponent: John O. Warner
Opponent: Carsten Heilmann
Pregnant women experience increased influenza related morbidity and mortality during seasonal influenza epidemics, and even graver outcomes during influenza pandemics.
Thus, even though the huge amount of data on clinical efficacy and effectiveness of influenza vaccine in pregnant women, there is limited information on the details of the immunological responses to influenza immunization in pregnant versus non-pregnant. We had the unique opportunity to study the H1N1pnd09 vaccination of pregnant and non-pregnant women in our unselected, prospective, clinical pregnancy-cohort: the Copenhagen Prospective Study on Asthma in Childhood 2010 (COPSAC2010). The timing of this enrolment and the pandemic provided for an “experiment of nature” in our population of subjects of whom half had completed pregnancy before the pandemic and the other half were pregnant while H1N1pnd09 virus was prevalent in the community.
Influenza is also a major cause of morbidity and hospitalization in infants younger than six months. In particular the 2009 pandemic caused more severe disease in the neonates and young infants than in older children, all unprotected from passive immunity to this novel virus. No vaccination is approved for infants younger than six months. Therefore influenza vaccination during pregnancy has been proposed as a safe way to protect infants, presumably by cocooning and from antibodies transmitted from the mother. Although, inheritance patterns of atopic and inflammatory diseases, and maternal atopic impact on neonatal immune signature in the airway of neonates implies that some immunological triggering factors during pregnancy may enhance changes in the immune system of the offspring. Influenza vaccination is generally considered safe for the pregnant mother and the fetus, but there is no published evidence on the possible effect on the neonatal immune status.
In this PhD thesis we aim to compare the immunogenicity of the H1N1pnd09 vaccine in pregnant versus non-pregnant women and to explore the immunological consequences of vaccination in the offspring.
In paper I, we conducted a randomized controlled clinical trial primarily to compare immunogenicity of the H1N1pnd09 vaccine in pregnant versus non-pregnant women; secondarily to study dose-related immune responses and adverse events to MF59-adjuvanted versus non- adjuvanted vaccine in pregnant recipients. The sero-conversion rate was significantly higher in non- pregnant women compared with pregnant women after receiving the same standard H1N1pnd09vaccine. Likewise geometric mean titres was nominally higher in the non-pregnant than in the pregnant women. Interestingly even after 10 months, both pregnant and non-pregnant women were protected against H1N1pnd09 according to the EMEA criteria with a HI titre of 40 or greater. Women receiving the non-adjuvanted vaccine had significantly fewer local reactions but similar rates of systemic reactions as women receiving the adjuvanted vaccine. There were no reports of serious adverse events in any of the groups.
In paper II, we compared the local immune signature of the airway mucosa and the incidence of infections in the first year of life in neonates of mothers receiving H1N1pnd09 vaccination during pregnancy versus neonates of mothers not vaccinated during pregnancy. Vaccination against influenza A(H1N1)pnd09 during pregnancy induces alternations in the primary mucosal line of defense in the upper airways of newborn children. TGF-β1 is up-regulated and other key-mediators are down-regulated suggesting a compromised local immune defense. This effect is enhanced the earlier in the pregnancy the woman is vaccinated. We found no changes in the incidence of infections in the first year of life in the children.
In conclusion, we find the immune response to the H1N1pnd09 vaccine in pregnant women may be diminished compared with non-pregnant women. Furthermore, H1N1pnd09 vaccination during pregnancy has a time dependent effect that up-regulates TGF-β1 and down-regulates key mediators of the protective immunity in the mucosal lining fluid of the neonate, but the infectious rate was not detectably affected. In this study we have shown for the first time that the fetal immune response is indeed affected by the maternal immune activation propagated by a vaccination. This is a very notable finding, underscoring the necessity for increasing the general insight into vaccination programs in pregnant women and the resulting influence on the general neonatal immunity, not only focusing on neonatal immunity against the specific disease and the vaccine antigens.