Philipp Lambach

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.

Effective vaccine safety systems in all countries: A challenge for more equitable access to immunization

Serious vaccine-associated adverse events are rare. To further minimize their occurrence and to provide adequate care to those affected, careful monitoring of immunization programs and case management is required. Unfounded vaccine safety concerns have the potential of seriously derailing effective immunization activities. To address these issues, vaccine pharmacovigilance systems have been developed in many industrialized countries. As new vaccine products become available to prevent new diseases in various parts of the world, the demand for effective pharmacovigilance systems in low- and middle-income countries (LMIC) is increasing. To help establish such systems in all countries, WHO developed the Global Vaccine Safety Blueprint in 2011. This strategic plan is based on an in-depth analysis of the vaccine safety landscape that involved many stakeholders. This analysis reviewed existing systems and international vaccine safety activities and assessed the financial resources required to operate them. The Blueprint sets three main strategic goals to optimize the safety of vaccines through effective use of pharmacovigilance principles and methods: to ensure minimal vaccine safety capacity in all countries; to provide enhanced capacity for specific circumstances; and to establish a global support network to assist national authorities with capacity building and crisis management. In early 2012, the Global Vaccine Safety Initiative (GVSI) was launched to bring together and explore synergies among on-going vaccine safety activities. The Global Vaccine Action Plan has identified the Blueprint as its vaccine safety strategy. There is an enormous opportunity to raise awareness for vaccine safety in LMIC and to garner support from a large number of stakeholders for the GVSI between now and 2020. Synergies and resource mobilization opportunities presented by the Decade of Vaccines can enhance monitoring and response to vaccine safety issues, thereby leading to more equitable delivery of vaccines worldwide.

A global review of national influenza immunization policies: Analysis of the 2014 WHO/UNICEF Joint Reporting Form on immunization.

Introduction The WHO recommends annual influenza vaccination to prevent influenza illness in high-risk groups. Little is known about national influenza immunization policies globally. Material and Methods The 2014 WHO/UNICEF Joint Reporting Form (JRF) on Immunization was adapted to capture data on influenza immunization policies. We combined this dataset with additional JRF information on new vaccine introductions and strength of immunization programmes, as well as publicly available data on country economic status. Data from countries that did not complete the JRF were sought through additional sources. We described data on country influenza immunization policies and used bivariate analyses to identify factors associated with having such policies. Results Of 194 WHO Member States, 115 (59%) reported having a national influenza immunization policy in 2014. Among countries with a national policy, programmes target specific WHO-defined risk groups, including pregnant women (42%), young children (28%), adults with chronic illnesses (46%), the elderly (45%), and health care workers (47%). The Americas, Europe, and Western Pacific were the WHO regions that had the highest percentages of countries reporting that they had national influenza immunization policies. Compared to countries without policies, countries with policies were significantly more likely to have the following characteristics: to be high or upper middle income (p < 0.0001); to have introduced birth dose hepatitis B virus vaccine (p < 0.0001), pneumococcal conjugate vaccine (p = 0.032), or human papilloma virus vaccine (p = 0.002); to have achieved global goals for diphtheria-tetanus-pertussis vaccine coverage (p < 0.0001); and to have a functioning National Immunization Technical Advisory Group (p < 0.0001). Conclusions The 2014 revision of the JRF permitted a global assessment of national influenza immunization policies. The 59% of countries reporting that they had policies are wealthier, use more new or under-utilized vaccines, and have stronger immunization systems. Addressing disparities in public health resources and strengthening immunization systems may facilitate influenza vaccine introduction and use.

Considerations of strategies to provide influenza vaccine year round

There is potential for influenza vaccine programmes to make a substantial impact on severe disease in low-resource settings, however questions around vaccine composition and programmatic issues will require special attention. Some countries may benefit from immunization programmes that provide year-round supply of vaccine; however the best way to ensure adequate vaccine supply has yet to be determined. In this report, we discuss vaccine composition, availability, and programmatic issues that must be considered when developing year-round influenza immunization programmes. We then explore how these considerations have influenced immunization practices in the Latin American region as a case study. We identify three different approaches to achieve year-round supply: (1) alternating between Northern Hemisphere and Southern Hemisphere formulations, (2) extending the expiration date to permit extended use of a single hemisphere formulation, and (3) local vaccine manufacture with production timelines that align with local epidemiology. Each approach has its challenges and opportunities. The growing data suggesting high influenza disease burden in low resource countries underscores the compelling public health need to determine the best strategies for vaccine delivery.

A systematic review of adverse events following immunization during pregnancy and the newborn period.

In 2013, the WHO Strategic Advisory Group of Experts on Immunization (SAGE) requested WHO to develop a process and a plan to move the maternal immunization agenda forward in support of an increased alignment of data safety evidence, public health needs, and regulatory processes. A key challenge identified was the continued need for harmonization of maternal adverse event following immunization (AEFI) research and surveillance efforts within developing and developed country contexts. We conducted a systematic review as a preliminary step in the development of standardized AEFI definitions for use in maternal and neonatal clinical trials, post-licensure surveillance, and other vaccine studies. We documented the current extent and nature of variability in AEFI definitions and adverse event reporting among 74 maternal immunization studies, which reported a total of 240 different types of adverse events. Forty-nine studies provided explicit AEFI case definitions describing 35 separate types of AEFIs. We identified variability in how AEFIs were determined to be present, in how AEFI definitions were applied, and in the ways that AEFIs were reported. Definitions for key maternal/neonatal AEFIs differed on four discrete attributes: overall level of detail, physiological and temporal boundaries and cut-offs, severity strata, and standards used. Our findings suggest that investigators may proactively address these inconsistencies through comprehensive and consistent reporting of AEFI definitions and outcomes in future publications. In addition, efforts to develop standardized AEFI definitions should generate definitions of sufficient detail and consistency of language to avoid the ambiguities we identified in reviewed articles, while remaining practically applicable given the constraints of low-resource contexts such as limited diagnostic capacity and high patient throughput.

Guideline for collection, analysis and presentation of safety data in clinical trials of vaccines in pregnant women.

Vaccination during pregnancy is increasingly being used as an effective approach for protecting both young infants and their mothers from serious infections. Drawing conclusions from published studies in this area can be difficult because of the inability to compare vaccine trial results across different studies and settings due to the heterogeneity in the definitions of terms used to assess the safety of vaccines in pregnancy and the data collected in such studies. The guidelines proposed in this document have been developed to harmonize safety data collection in all phases of clinical trials of vaccines in pregnant women and apply to data from the mother, fetus and infant. Guidelines on the prioritization of the data to be collected is also provided to allow applicability in various geographic, cultural and resource settings, including high, middle and low-income countries.

Seasonal influenza vaccine policy, use and effectiveness in the tropics and subtropics – a systematic literature review

The evidence needed for tropical countries to take informed decisions on influenza vaccination is scarce. This article reviews policy, availability, use and effectiveness of seasonal influenza vaccine in tropical and subtropical countries.

Key terms for the assessment of the safety of vaccines in pregnancy: Results of a global consultative process to initiate harmonization of adverse event definitions

BACKGROUND The variability of terms and definitions of Adverse Events Following Immunization (AEFI) represents a missed opportunity for optimal monitoring of safety of immunization in pregnancy. In 2014, the Brighton Collaboration Foundation and the World Health Organization (WHO) collaborated to address this gap. METHODS Two Brighton Collaboration interdisciplinary taskforces were formed. A landscape analysis included: (1) a systematic literature review of adverse event definitions used in vaccine studies during pregnancy; (2) a worldwide stakeholder survey of available terms and definitions; (3) and a series of taskforce meetings. Based on available evidence, taskforces proposed key terms and concept definitions to be refined, prioritized, and endorsed by a global expert consultation convened by WHO in Geneva, Switzerland in July 2014. RESULTS Using pre-specified criteria, 45 maternal and 62 fetal/neonatal events were prioritized, and key terms and concept definitions were endorsed. In addition recommendations to further improve safety monitoring of immunization in pregnancy programs were specified. This includes elaboration of disease concepts into standardized case definitions with sufficient applicability and positive predictive value to be of use for monitoring the safety of immunization in pregnancy globally, as well as the development of guidance, tools, and datasets in support of a globally concerted approach. CONCLUSIONS There is a need to improve the safety monitoring of immunization in pregnancy programs. A consensus list of terms and concept definitions of key events for monitoring immunization in pregnancy is available. Immediate actions to further strengthen monitoring of immunization in pregnancy programs are identified and recommended.

A global perspective of maternal influenza immunization.

The World Health Organization (WHO) influenza vaccine polcy recommendations aim to protect vulnerable high-risk groups rom severe disease. In a 2012 update of its influenza vaccine posiion, WHO recommends that countries considering the initiation r expansion of programmes for seasonal influenza vaccination hould prioritize pregnant women over other high risk groups young children, the elderly, persons with certain chronic illnesses, nd health care workers) [1]. The recommendation was based n numerous factors, including influenza disease risk in pregnant omen and among their young children in the first months after irth, vaccine safety and effectiveness, as well the programmatic pportunities to reach this population in lowand middle-income ountries. This review describes the advancements made in the eld of maternal influenza immunization since the 2012 WHO polcy recommendation, as well as the evidence gaps that remain. We ocus on the evidence needs to review maternal influenza immuization in the poorest countries—many of which have not yet ntroduced influenza vaccine programs. In 2013, GAVI, the Vaccine Alliance reviewed maternal influenza mmunization for possible inclusion in its vaccine investment portolio for low-income countries. While GAVI opted not to invest n the strategy, its review was generally positive. GAVI vacine program impact models estimated that maternal influenza mmunization could avert around 45 deaths per 100,000 perons vaccinated in GAVI-eligible countries, similar to the expected

Association Between Pandemic Influenza A(H1N1) Vaccination in Pregnancy and Early Childhood Morbidity in Offspring.

Importance Several studies investigating potential adverse effects of the pandemic A(H1N1) vaccine have supported that influenza A(H1N1) vaccination does not increase the risk for major pregnancy and birth adverse outcomes, but little is known about possible adverse effects in offspring of A(H1N1)-vaccinated mothers beyond the perinatal period and into early childhood. Objective To evaluate whether pandemic influenza A(H1N1) vaccination in pregnancy increases the risk for early childhood morbidity in offspring. Design, Setting, and Participants Register-based cohort study comprising all live-born singleton children in Denmark from pregnancies overlapping the A(H1N1) influenza vaccination campaign in Denmark, from November 2, 2009, to March 31, 2010. From a cohort of 61 359 pregnancies, offspring exposed and unexposed to the influenza A(H1N1) vaccine during pregnancy were matched 1:4 on propensity scores. Exposure Vaccination in pregnancy with a monovalent inactivated AS03-adjuvanted split virion influenza A(H1N1)pdm09 vaccine (Pandemrix; GlaxoSmithKline Biologicals). Main Outcomes and Measures Rate ratios of hospitalization in early childhood until 5 years of age. Hospitalization was defined as (1) first inpatient hospital admission, (2) all inpatient hospital admissions, and (3) first hospital contact for selected diseases, which included individual infectious diseases and individual neurologic, autoimmune, and behavioral conditions. Results The mean (SD) age at end of follow-up was 4.6 (0.40) years for the 61 359 children included in the study. In the cohort, the mothers of 55 048 children were unvaccinated, 349 mothers were vaccinated in the first trimester, and 5962 mothers were vaccinated in the second or third trimesters. Children exposed in the first trimester were not more likely to be hospitalized in early childhood than unexposed children (hospitalization rates per 1000 person-years, 300.6 for exposed vs 257.5 for unexposed; rate ratio, 1.17; 95% CI, 0.94-1.45). Similarly, children exposed in the second or third trimester were not more likely to be hospitalized in early childhood than unexposed children (hospitalization rates per 1000 person-years, 203.6 for exposed vs 219.3 for unexposed; rate ratio, 0.93; 95% CI, 0.87-0.99). This 7% decreased risk was primarily a result of reduced risks for infectious disease–related hospitalizations. Conclusions and Relevance To our knowledge, this is the most comprehensive study to date of potential adverse effects manifesting after the perinatal period. We detected no increased risk for early childhood morbidity. These results support the safety profile of the influenza A(H1N1) vaccine used in pregnancy.