Influenza vaccine for pregnant women in resource-constrained countries: a review of the evidence to inform policy decisions

Seasonal influenza is responsible for three to five million severe cases of disease annually, and up to 500,000 deaths worldwide. Pregnant women and infants suffer disproportionately from severe outcomes of influenza. The excellent safety profile and reliable immunogenicity of inactivated influenza vaccine support WHO recommendations that pregnant women be vaccinated to decrease complications of influenza disease during pregnancy. Nevertheless, influenza vaccine is not routinely used in most low-and middle-income countries and is not widely used in pregnant women worldwide.Two recent prospective, controlled trials of maternal influenza vaccination in Bangladesh and US Native American reservations demonstrated that inactivated influenza vaccine given to pregnant women can decrease laboratory-confirmed influenza virus infection in their newborn children. These studies support consideration of the feasibility of targeted influenza vaccine programs in resource-constrained countries.Platforms exist for the delivery of influenza vaccine to pregnant women worldwide. Even in the least developed countries, an estimated 70% of women receive antenatal care, providing an opportunity for targeted influenza vaccination. Challenges to the introduction of maternal influenza vaccination in resource-constrained countries exist, including issues regarding vaccine formulation, availability, and cost. Nonetheless, maternal influenza vaccination remains an important and potentially cost-effective approach to decrease influenza morbidity in two high-risk groups - pregnant women and young infants.     

Maternal immunization in Malawi: A mixed methods study of community perceptions,programmatic considerations,and recommendations for future planning

BackgroundSafe, effective vaccines are given to pregnant women to protect their infants and/or themselves against certain infectious agents; however, apart from tetanus vaccination, maternal immunization in low- and middle-income countries (LMICs) remains low. Tetanus toxoid vaccine is integrated into antenatal care services in Malawi with high coverage and provides an opportunity to identify factors that facilitate successful immunization delivery to pregnant women in LMICs.MethodsPATH and the University of Malawi’s Centre for Social Research conducted a mixed-methods study in 2015 to document community perceptions of maternal immunization, using tetanus vaccine as an example, and to identify factors perceived to be important to successfully introducing other maternal vaccines, such as influenza vaccine, in Malawi. We conducted 18 focus group discussions with pregnant and recently pregnant women and their family members and 76 semi-structured interviews with pregnant and recently pregnant women, community leaders, health workers, public health program managers, non-governmental partners, and policy makers.ResultsWe identified factors perceived to support the introduction of new maternal vaccines, including strong maternal vaccine acceptance in the community, an existing strategy for maternal tetanus vaccine delivery, and positive health workers’ views about the introduction of additional maternal vaccines. Potential challenges to adoption and acceptance included identifying and tracking the target population and monitoring adverse events, and the need to ensure operational capacity of the health system to support the introduction and wide-scale use of an additional vaccine. For influenza vaccine specifically, additional challenges included limited awareness of influenza disease and its low prioritization among health needs.ConclusionsLessons from the successful delivery of maternal tetanus immunization in Malawi may be informative for similar countries considering new vaccines for pregnant women or striving to optimize the delivery of those currently provided.     

Non-adjuvanted 2009 influenza A (H1N1)v vaccine in pregnant women: the results of a French prospective descriptive study

In 2009, during the influenza A (H1N1)v pandemic, the French Health authorities recommended influenza immunisation for pregnant women because of the higher risk of serious influenza outcomes in that population. Thus, the non-adjuvanted inactivated influenza vaccine Panenza^® was administered to French women from the second trimester of pregnancy. Several studies suggest that inactivated seasonal influenza vaccines are safe during pregnancy but there are few data about the effects of new A (H1N1)vaccines (new antigen) on pregnant women.

Objective

The aim of the present prospective study was to describe pregnancy outcomes among women vaccinated with non-adjuvanted influenza vaccines in South Western France.

Methods

the study ran from November 2009 to February 2010 and included, on a voluntary basis, pregnant women who were vaccinated against A (H1N1) influenza in vaccination clinics or maternity wards.

Results

569 pregnant women were monitored until delivery. Compared with the general population, the risks of maternal conditions, malformations and neonatal conditions were not statistically different.

Conclusion

This study does not reveal any sign of safety concerns regarding the effects of the vaccine on pregnancy outcomes.     

Protection of pregnant mice,fetuses and neonates from lethality of H5N1 influenza viruses by maternal vaccination

The highly pathogenic H5N1 influenza viruses are one of candidates for the next pandemic. Information on protective immunity for pregnant animals by vaccination against the H5N1 influenza virus is limited. Here, we show that the immunization of pregnant mice with inactivated H5N1 influenza vaccine protects them, their fetuses, and their infant mice from H5N1 influenza viruses. Pregnant mice immunized with two doses of H5N1 influenza vaccine were protected from homologous infections of H5N1 influenza viruses with no viruses detected in fetuses, and that they were protected upto 30% from heterologous infections of H5N1 influenza viruses with viruses detected in fetuses. The infant mice born to mothers immunized with H5N1 influenza vaccine were fully protected from infections of H5N1 influenza viruses for upto 4 weeks of age. The protection of infant mice was closely related to the presence of IgG2a antibody in lung, heart, and rectum tissues. Our results suggest that maternal vaccination may be critical for protecting pregnant animals, their fetuses, and their infant mice from lethal infections of H5N1 influenza viruses.     

Mother-infant vaccination with pneumococcal polysaccharide vaccine: persistence of maternal antibodies and responses of infants to vaccination

Protection against pneumococcal infection early in life is needed. This could be achieved by maternal vaccination or by starting infant vaccinations as early as possible. In an open controlled study, pregnant women received both 23-valent pneumococcal polysaccharide vaccine (PPV), Haemophilus influenzae type b conjugate vaccine and tetanus toxoid or tetanus toxoid alone. Infants received PPV at 7 or 17 weeks and the second dose at 3 years of age. Antibodies to six pneumococcal serotypes were measured with the non-22F and 22F enzyme immunoassays (EIA). Elevated antibody concentrations after maternal vaccination persisted in infants until 4 months of age. Infants responded to serotypes 1 and 5, but not to serotypes 6B, 14, 18C and 19F. High maternal antibody concentrations at early age reduced the responses, but not the antibody concentrations, of infants to PPV. The percentages of infants with concentrations >0.35 μg/ml and >1 μg/ml were high at birth, but decreased by age during the first 10 months of life. Revaccination with PPV at 3 years of age induced a good immune response.     

Report of the 7th meeting on Evaluation of Pandemic Influenza Vaccines in Clinical Trials, World Health Organization, Geneva, 17-18 February 2011

On February 17-18, 2011, the World Health Organization convened the 7th meeting on “The Evaluation of Pandemic Influenza Vaccines in Clinical Trials” to review the progress made on pandemic A (H1N1) 2009 vaccines and the evaluation of their effectiveness in the field, especially in children less than 3 years of age and in pregnant women. Other topics to be addressed included a comparison of egg- and cell culture-based influenza vaccines, technical issues related to vaccine strain development and vaccine potency, and the status of development of prototype influenza vaccines using new technologies. Pandemic A (H1N1) vaccines were safe in young children, pregnant women and immunocompromized individuals. Overall effectiveness of inactivated A (H1N1) vaccines for all ages was found to vary between 72% and 100% in different countries and with different vaccine preparations. Effectiveness of pandemic A (H1N1) 2009 live attenuated vaccine was estimated to be approximately 80% in pediatric populations in the USA. A single dose of inactivated vaccine adjuvanted with AS03, MF59 or AF03 induced protective immunity in young children and pregnant women. However, unadjuvanted vaccines as well as low dose adjuvanted vaccines (1.9 μg HA) required two doses to elicit protective antibody levels in these populations. Clinical trials of influenza vaccines developed using new technologies showed they were well tolerated and induced antibody and/or T cell immune responses to viral proteins. Further studies are warranted to validate novel immunological criteria for evaluation and licensing of such new influenza vaccine concepts. On the regulatory side, work should be undertaken to harmonize the results of serological tests used to evaluate the immunogenicity of traditional influenza vaccines.     

Identifying ways to increase seasonal influenza vaccine uptake among pregnant women in China: A qualitative investigation of pregnant women and their obstetricians

BackgroundPregnant women are at higher risk for complications from influenza infection. Nevertheless, seasonal influenza vaccination among pregnant women in China is low. A better understanding of perceptions of pregnant women and their physicians, and factors influencing decisions about receiving seasonal influenza vaccine could be used to develop effective strategies for improving seasonal influenza vaccine uptake during pregnancy.MethodsWe recruited pregnant women from 9 hospitals located in 5 cities across China to participate in focus group interviews. Obstetricians from the same hospitals were recruited for one on one in-depth interviews. We collected information about perceptions of barriers and motivating factors for utilizing seasonal influenza vaccine during pregnancy. We systematically analyzed the information using qualitative methods.ResultsWe conducted 18 focus groups with 108 pregnant women and interviewed 18 obstetricians. Awareness about the use of influenza vaccine during pregnancy was minimal in both subject groups. None of the pregnant women had received influenza vaccine during pregnancy and none of the obstetricians had recommended influenza vaccine for their patients. Both groups noted insufficient knowledge about influenza infection and benefits of the vaccine, concerns about vaccine safety, and lack of local data related to vaccine use in Chinese pregnant women. Obstetricians cited the lack of a national policy as a major barrier to recommending seasonal influenza vaccine to pregnant women. Pregnant women cited not receiving a recommendation for vaccination from healthcare workers as an additional barrier.ConclusionOur findings highlight the immediate need to increase awareness and knowledge about the risks of influenza infection and the benefits and safety of seasonal influenza vaccination among both pregnant women and obstetricians in China. Obstetricians interviewed stated that the development and implementation of a national policy prioritizing pregnant women for seasonal influenza vaccination would facilitate their willingness to recommend seasonal influenza vaccine to pregnant women.     

Perinatal survival and health after maternal influenza A(H1N1)pdm09 vaccination: A cohort study of pregnancies stratified by trimester of vaccination

Large cohort studies demonstrated the safety of vaccination with the AS03 adjuvanted pandemic influenza vaccine, but data on first trimester vaccination safety are limited.We conducted a nationwide register-based retrospective cohort study in Finland, included singleton pregnancies present on 01 November 2009 and followed them from 01 November 2009 until delivery. Pregnancies with abortive outcome, pregnancies that started before 01 February 2009 and pregnancies of women, who received the AS03 adjuvanted pandemic influenza vaccine prior to the onset of pregnancy, were excluded. Our main outcome measures were hazard ratios comparing the risk of stillbirth, early neonatal death, moderately preterm birth, very preterm birth, moderately low birth weight, very low birth weight, and being small for gestational age between pregnancies exposed and unexposed to maternal influenza A(H1N1)pdm09 vaccination.The study population comprised 43,604 pregnancies; 34,241 (78.5%) women were vaccinated at some stage during pregnancy. The rates of stillbirth, early neonatal death, moderately preterm birth, and moderately low birth weight were similar between pregnant women exposed and unexposed to influenza A(H1N1)pdm09 vaccination. After adjusting for known risk factors, the relative rates were 0.90 (95% confidence interval 0.55–1.45) for very preterm birth, 0.84 (0.61–1.16) for very low birth weight, and 1.17 (0.98–1.40) for being small for gestational age. Also, in the subanalysis of 7839 women vaccinated during the first trimester, the rates did not indicate that maternal vaccination during the first trimester had any adverse impact on perinatal survival and health.The risk of adverse pregnancy outcomes was not associated with the exposure to the AS03 adjuvanted pandemic influenza vaccine. This study adds reassuring evidence on the safety of AS03 adjuvanted influenza vaccines when given in the first trimester and supports the recommendation of influenza vaccination to all pregnant women through all stages of pregnancy.     

Safety and immunogenicity of seasonal trivalent inactivated influenza vaccines in pregnant women

BackgroundIn the United States, seasonal inactivated influenza vaccine (IIV) is recommended for pregnant women; however, in early 2009, immunization rates were low, partly due to limited prospective data and concerns about vaccine safety.ObjectiveWe conducted a randomized study of two licensed seasonal trivalent IIVs (IIV3) to assess their safety and immunogenicity in pregnant women.Study DesignIn this prospective, randomized clinical study, 100 pregnant women, 18–39 years of age and ≥14 weeks gestation received a single intramuscular dose of 2008–2009 Fluzone® or Fluarix®. Injection site and systemic reactions were recorded for 7 days after vaccination and serious adverse events (SAEs) and pregnancy outcomes were documented. Serum samples collected before and 28 days after vaccination were tested for hemagglutination inhibition (HAI) antibody levels.ResultsThe majority of the injection site and systemic reactions were mild and self-limited after both vaccines. No fever ≥100 °F was reported. There were no vaccine-associated SAEs. Immune responses to influenza vaccine antigens were similar for the two study vaccines, with robust HAI responses against influenza A strains, and relatively lower responses for influenza B strains.ConclusionSeasonal inactivated influenza vaccines were well tolerated and immunogenic in pregnant women.

• ClinicalTrials.gov identifier NCT00905125.

Synopsis: In this prospective clinical trial, we demonstrated that immunization with seasonal trivalent, inactivated influenza vaccine in the second and third trimester of pregnancy is immunogenic and safe.     

Lessons from pandemic influenza A(H1N1): the research-based vaccine industry's perspective

As A(H1N1) influenza enters the post-pandemic phase, health authorities around the world are reviewing the response to the pandemic. To ensure this process enhances future preparations, it is essential that perspectives are included from all relevant stakeholders, including vaccine manufacturers. This paper outlines the contribution of R&D-based influenza vaccine producers to the pandemic response, and explores lessons that can be learned to improve future preparedness.The emergence of 2009 A(H1N1) influenza led to unprecedented collaboration between global health authorities, scientists and manufacturers, resulting in the most comprehensive pandemic response ever undertaken, with a number of vaccines approved for use three months after the pandemic declaration. This response was only possible because of the extensive preparations undertaken during the last decade.During this period, manufacturers greatly increased influenza vaccine production capacity, and estimates suggest a further doubling of capacity by 2014. Producers also introduced cell-culture technology, while adjuvant and whole virion technologies significantly reduced pandemic vaccine antigen content. This substantially increased pandemic vaccine production capacity, which in July 2009 WHO estimated reached 4.9 billion doses per annum. Manufacturers also worked with health authorities to establish risk management plans for robust vaccine surveillance during the pandemic. Individual producers pledged significant donations of vaccine doses and tiered-pricing approaches for developing country supply.Based on the pandemic experience, a number of improvements would strengthen future preparedness. Technical improvements to rapidly select optimal vaccine viruses, and processes to speed up vaccine standardization, could accelerate and extend vaccine availability. Establishing vaccine supply agreements beforehand would avoid the need for complex discussions during a period of intense time pressure.Enhancing international regulatory co-operation and mutual recognition of approvals could accelerate vaccine supply, while maintaining safety standards. Strengthening communications with the public and healthcare workers using new approaches and new channels could help improve vaccine uptake. Finally, increasing seasonal vaccine coverage will be particularly important to extend and sustain pandemic vaccine production capacity.     

Pandemic influenza vaccination: lessons learned from Latin America and the Caribbean

In April 2009, the World Health Organization (WHO) reported the emergence of a new influenza (H1N1) virus which led to the first pandemic declaration of the 21st century. Most countries in Latin America and the Caribbean (LAC) had a national preparedness plan in place at this time; however, the vaccination component of such plans was largely undeveloped. Nevertheless, countries were able to capitalize on the infrastructure of their immunization programs and widespread experience utilizing the seasonal influenza vaccine to prepare rapidly, developing H1N1 vaccination plans targeting individuals with chronic disease, pregnant women and health care workers, among others. In LAC vaccine was acquired through three mechanisms: the Pan American Health Organization's Revolving Fund, direct manufacturer purchase, and WHO donations. Vaccine access was not equitable both in quantity of vaccine available and timeless of vaccine availability. As of December 2010, an estimated 145 million doses had been administered in LAC. Despite high regional coverage, there were large variations in coverage at the national level; pregnant women had the lowest coverage, despite their high risk for morbidity and mortality. The number of severe adverse events reported in LAC was similar to those expected with the seasonal influenza vaccine. Risk communication was one of the key challenges countries faced, mainly due to concerns and misinformation spread regarding vaccine safety. Countries and the international community need to learn from the experiences gained during H1N1 vaccination in order to be better prepared for the next pandemic.     

Safety of immunization during pregnancy: A review of the evidence of selected inactivated and live attenuated vaccines

Vaccine-preventable infectious diseases are responsible for significant maternal, neonatal, and young infant morbidity and mortality. While there is emerging scientific evidence, as well as theoretical considerations, indicating that certain vaccines are safe for pregnant women and fetuses, policy formulation is challenging because of perceived potential risks to the fetus.This report presents an overview of available evidence on pregnant women vaccination safety monitoring in pregnant women, from both published literature and ongoing surveillance programs. Safety data were reviewed for vaccines against diseases which increase morbidity in pregnant women, their fetus or infant as well as vaccines which are used in mass vaccination campaigns against diseases. They include inactivated seasonal and pandemic influenza, mono- and combined meningococcal polysaccharide and conjugated vaccines, tetanus toxoid and acellular pertussis combination vaccines, as well as monovalent or combined rubella, oral poliomyelitis virus and yellow fever vaccines. No evidence of adverse pregnancy outcomes has been identified from immunization of pregnant women with these vaccines.     

Failure of the vaccination campaign against A(H1N1) influenza in pregnant women in France: Results from a national survey

Background and objective

Pregnant women were a priority group for vaccination during the 2009 A(H1N1) influenza pandemic. In France, vaccination was organized in ad hoc centers. Women received vouchers by mail and were given a non-adjuvanted vaccine. Our objective was to assess the national vaccination rate among pregnant women and to determine the association of vaccination with maternal characteristics, prenatal care, and pregnancy-related health behaviors.

Method

Data came from a national representative sample of women who gave birth in March 2010 (N = 13 453) and were interviewed in the hospital before discharge; they were in the second trimester of pregnancy during the vaccination campaign. Associations between vaccination and socio-demographic and medical characteristics, region of residence, care providers, and preventive behaviors were assessed with bivariable analyses and logistic regression models.

Results

Vaccine coverage was 29.3% (95% CI: 28.6–30.1). The main reason for not being vaccinated was that women did not want this immunization (91%). In adjusted analyses, vaccination was more frequent in women who were older, employed, born in France, with a parity of 1 or 2 and specific favourable health behaviors. The adjusted odds ratio for women with a postgraduate educational level was 4.1 (95% CI: 3.5–4.8) compared to those who did not complete high school. Women with additional risk factors for complications from A(H1N1) infection had a vaccination rate similar to that of other women.

Conclusion

The vaccination campaign resulted in poor vaccination coverage, strong social inequalities, and no special protection for pregnant women at the highest risk of complications. These findings provide essential information for the organization of future vaccination campaigns.     

Barriers to influenza vaccination among pregnant women

Objective

Despite pregnant women's increased morbidity and mortality from influenza, vaccination rates remain low. This study intended to evaluate barriers to pregnant women's uptake of influenza vaccine.

Study design

A survey was designed that assessed participant demographics, knowledge, beliefs, attitudes, and general experiences with seasonal and 2009 novel H1N1 influenza. Associations between patient characteristics and vaccine uptake were then assessed.

Results

88 women completed the survey. Women who correctly answered >75% of knowledge questions regarding influenza were significantly more likely to accept the influenza vaccine (seasonal: p = 0.04, H1N1: p < 0.01). Conversely, patients who declined the vaccine were more likely to hold false beliefs, such as perceiving that the vaccine was not protective (seasonal: p < 0.01, H1N1: p < .01) and that they were not at risk for influenza (seasonal: p <  0.01).

Conclusion

The reasons for influenza vaccine declination in pregnant patients include lower levels of knowledge and unfavorable attitudes regarding the safety and efficacy of the vaccine, and suggest the importance of education as a tool to improve vaccination uptake     

Implementation of maternal influenza immunization in El Salvador: Experiences and lessons learned from a mixed-methods study

IntroductionThe World Health Organization (WHO) recommends that countries prioritize pregnant women for influenza vaccination, yet few low- or middle-income countries (LMICs) have implemented maternal influenza immunization programs. To inform vaccine decision-making and operational planning in LMICs, there is a need to document and share experiences from countries that provide seasonal influenza vaccine to pregnant women, particularly those with high coverage, like El Salvador.MethodsIn 2015 and 2016, PATH and country researchers conducted a mixed-methods study to document the experience and lessons learned from maternal influenza immunization delivery and acceptance in El Salvador as part of a collaborative effort between WHO and PATH. Researchers conducted focus group discussions, semi-structured interviews, antenatal clinic exit interviews, and key informant interviews with 326 participants from two municipalities in each of the country’s three regions. Respondents included pregnant and recently pregnant women, family members, community leaders, health personnel, public health managers and partners, and policymakers.ResultsFactors perceived as positively influencing maternal influenza immunization delivery and acceptance in El Salvador include the use of multiple vaccine delivery strategies, targeted education and community engagement efforts, and a high degree of trust between the community and health care providers. Influenza vaccine acceptance by pregnant women is high and has improved over time, largely attributed to education targeting health care advisors. Perceived challenges to pregnant women receiving health care and vaccination include the need for permission to attend services and limited access to health services in insecure areas related to the presence of criminal gang activity.ConclusionsWe identified approaches and barriers perceived to affect maternal influenza vaccine delivery in El Salvador. This information will be useful to public health decision-makers and implementers in El Salvador and other countries considering introduction of new maternal vaccines or striving to increase coverage of vaccines currently provided.     

Multi-tiered intervention to increase maternal immunization coverage: A randomized,controlled trial

ObjectiveTo evaluate the impact of a multi-component intervention package of maternal immunization uptake in obstetric care clinics.MethodsIn a multi-level, cluster- and individually-randomized controlled trial we implemented an evidence-based intervention that targeted practice-, provider- and patient-level barriers to vaccine uptake. Obstetric practices were randomized to receive the practice and provider-level interventions or continue their normal standard of care. We enrolled pregnant women at practices in Georgia and Colorado and randomized women into patient-level intervention and control groups, resulting in four study arms. The primary outcomes were receipt of the influenza and tetanus, diphtheria and acellular pertussis (Tdap) vaccines during pregnancy. A sample size of 550 women per arm (2200 total) was planned and enrolled to compare the intervention between the four study arms.ResultsBetween June 2017 and July 2018, 4907 women were screened and 2200 women were randomized, 550 to each of the four study arms. We were unable to follow-up with 108 women, for a final sample size of 2092. Sample characteristics and sample size were similar among study arms. There was no significant increase in Tdap or influenza vaccine uptake overall. Among women who had no intention of or were unsure about receiving the influenza vaccine during pregnancy, those who received just the patient-level intervention were 61% more likely to receive the influenza vaccine than those in the control arm (Relative risk: 1.61; 95% Confidence Interval: 1.18–2.21). There was no significant difference in vaccine uptake for either influenza or tetanus, diphtheria and acellular pertussis between the four arms of the study.ConclusionsThis trial highlights the need for more targeted interventions to improve vaccine uptake. Future work should focus on clinics with low baseline vaccine uptake and the patient-level intervention should be expanded and targeted towards women with low vaccine confidence.     

Safety of tetanus,diphtheria, acellular pertussis (Tdap) vaccination during pregnancy

The objective of this study was to evaluate the safety of prenatal tetanus, diphtheria, acellular pertussis (Tdap) vaccination. This cohort study was conducted among pregnant members at Kaiser Permanente Southern California (KPSC). The exposed cohort consisted of women who received Tdap vaccine on or after the 27th week of pregnancy between January 2018 and January 2019. The unexposed cohort consisted of matched women who were pregnant between January 2012 and December 2014 and were not vaccinated with any Tdap vaccine throughout their pregnancy. Maternal and infant characteristics and pre-specified endpoints were collected through automated data and review of the electronic health records. Unadjusted and adjusted relative risks (aRRs) with confidence intervals (CIs) were estimated by Poisson regression. Non-inferiority testing (i.e., to rule out a two-fold increase) was conducted for primary endpoints with adjustment for multiplicity. Superiority testing was conducted without multiplicity adjustment for secondary endpoints. The analysis consisted of 16,606 pairs of Tdap recipients and unexposed pregnant women. For the primary endpoints, the aRR for preeclampsia/eclampsia was 1.38 (98.75% CI:1.21–1.58) and the aRR for intrauterine infection was 1.28 (98.75% CI:1.12–1.47). These increases were consistent with the background increasing trend of these diagnoses among all pregnant women at KPSC since 2011, and the upper limit of the 98.75% CI of both aRRs did not exceed the pre-specified threshold of 2. No increased risks of small for gestational age (aRR = 1.04, 98.75% CI:0.94–1.16) or preterm delivery (aRR = 0.71, 98.75% CI:0.64–0.78) were observed. No evidence of increased risks for secondary endpoints, including poor fetal growth, preterm pre-labor rupture of membranes, stillbirth/fetal death, placental abruption, transfusion during delivery hospitalization, and neonatal death, was observed. Prenatal Tdap vaccination after the 27th week of pregnancy was not associated with increased risks of pre-specified maternal and infant outcomes, supporting the safety of Tdap vaccination during pregnancy.     

Influenza vaccine use to protect healthy children: A debated topic

At the beginning of this century, a number of studies suggested that in healthy children, particularly those <2 years of age, influenza could have a serious and complicated course, as it frequently led to hospitalization and sometimes, albeit rarely, to death. Moreover, pre-schoolers and school-age children were found to be among the most important causes of influenza transmission to the community, as they shed the virus for a longer time than adults and had frequent contact with greater numbers of individuals through day-care and school. These findings led a number of health authorities to modify the official recommendations regarding the use of influenza vaccine in healthy children. Several factors seem to indicate that vaccination against influenza in healthy children of any age and in pregnant women could be effective in preventing the disease in the entire paediatric population and in providing herd immunity in adults and old people as well. The direct advantages of the vaccine seem greater in younger subjects, particularly those <2–3 years of age. Vaccination of older children is considered effective by most experts, but high vaccination coverage of these subjects has been difficult to attain. Similar difficulties have been identified for the vaccination of pregnant women. These challenges can be overcome, at least in part, by appropriate information and accurate evaluations of available data. In addition, further studies specifically designed to clarify unresolved problems regarding vaccine use in paediatric and pregnant populations are needed to convince reluctant health authorities. More effective vaccines for younger children as well as improved availability of data regarding the optimal time period for vaccine administration in pregnant women appear relevant in this regard.     

Reports of cell-based influenza vaccine administered during pregnancy in the Vaccine Adverse Event Reporting System (VAERS), 2013–2020

BackgroundIn November 2012, the first cell cultured influenza vaccine, a trivalent subunit inactivated influenza vaccine (Flucelvax(®), ccIIV3), was approved in the United States for adults aged ≥18 years. A quadrivalent version (ccIIV4) was later approved in 2016 and replaced ccIIV3. The safety of ccIIV3 or ccIIV4 (ccIIV) was not assessed for pregnant women or their infants during pre-licensure studies.ObjectiveTo assess the safety of ccIIV administered during pregnancy in pregnant women and their infants whose reports were submitted to VAERS during 2013–2020.Material and methodsWe searched VAERS for United States reports of adverse events (AEs) in pregnant women who received ccIIV from 1 July 2013 through 31 May 2020. Clinicians reviewed reports and available medical records and assigned a primary clinical category for each report. Reports were coded as serious based on the Code of Federal Regulations definition.ResultsVAERS received 391 reports following ccIIV administered to pregnant women. Twenty-four (6.1%) were serious. Two neonatal deaths were reported. No maternal deaths occurred. Among reports with trimester information (n = 340), ccIIV was administered during the second trimester in 170 (50%). The most frequent pregnancy-specific AE was premature delivery in 85 (21.7%) reports, followed by dysmature placenta in 13 (3.3%) and pre-eclampsia/eclampsia in ten (2.3%). The most common non-pregnancy specific conditions were infectious conditions in 32 (8.2%). Among infant conditions, low birth weight was reported in 62 (15.9%) reports. Fifteen birth defects were reported; in 12 with gestational age information, administration of the vaccine occurred late in the second trimester or later.ConclusionsReview of maternal ccIIV reports in VAERS was not unexpectedly different from other maternal influenza vaccine safety VAERS reviews.     

Declining responsiveness to influenza vaccination with progression of human pregnancy

BackgroundInfluenza immunization is universally recommended during pregnancy to protect mothers and their offspring. However, pregnancy-induced shifts in vaccine responsiveness remain poorly defined.MethodsQuantitative and qualitative shifts in the serological response to influenza vaccination were evaluated in healthy women throughout the course of pregnancy. Serum was obtained before and after vaccination among 71 pregnant and 67 non-pregnant women during the 2011–12 and 2012–13 influenza seasons. Serum hemagglutination inhibition (HAI) assay was used to investigate anti-influenza antibody responses by comparing pre-vaccine and post-vaccine geometric mean titers (GMTs) between groups for each antigen. IgG1, IgG2, IgG3, and IgG4 anti-influenza titers were also evaluated by enzyme-linked immunosorbent assay (ELISA). Pregnancy induced shifts in HAI titers and levels of each anti-influenza antibody isotype were evaluated using linear regression models.ResultsPost-vaccine GMTs at day 28 were significantly reduced for women vaccinated during pregnancy for A/California (H1N1) in 2011 (p = 0.027), A/Perth (H3N2) in 2011 (p = 0.037), and B/Wisconsin in 2012 (p = 0.039). Vaccine responses progressively declined with the initiation of vaccination later in pregnancy. Anti-H1N1 IgG1, IgG2, and IgG3 titers were reduced in pregnant women compared to non-pregnant controls, and these titers declined with pregnancy progression. The most striking differences were found for anti-H1N1 IgG1, where titers decreased by approximately 7% each week throughout pregnancy.ConclusionsHAI responses elicited by immunization were significantly reduced during pregnancy for three different influenza vaccine antigens. Anti-H1N1 IgG1 was significantly lower in pregnant women and decreased throughout the course of pregnancy. Waning serological responsiveness to influenza vaccination with the progression of human pregnancy has important translational implications for when immunization should be optimally administered during pregnancy.