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Background: The Global COVID Vaccine Safety (GCoVS) Project, established in 2021 under the multinational Global Vaccine Data Network™ (GVDN®), facilitates comprehensive assessment of vaccine safety. This study aimed to evaluate the risk of adverse events of special interest (AESI) following COVID-19 vaccination from 10 sites across eight countries., Methods: Using a common protocol, this observational cohort study compared observed with expected rates of 13 selected AESI across neurological, haematological, and cardiac outcomes. Expected rates were obtained by participating sites using pre-COVID-19 vaccination healthcare data stratified by age and sex. Observed rates were reported from the same healthcare datasets since COVID-19 vaccination program rollout. AESI occurring up to 42 days following vaccination with mRNA (BNT162b2 and mRNA-1273) and adenovirus-vector (ChAdOx1) vaccines were included in the primary analysis. Risks were assessed using observed versus expected (OE) ratios with 95 % confidence intervals. Prioritised potential safety signals were those with lower bound of the 95 % confidence interval (LBCI) greater than 1.5., Results: Participants included 99,068,901 vaccinated individuals. In total, 183,559,462 doses of BNT162b2, 36,178,442 doses of mRNA-1273, and 23,093,399 doses of ChAdOx1 were administered across participating sites in the study period. Risk periods following homologous vaccination schedules contributed 23,168,335 person-years of follow-up. OE ratios with LBCI > 1.5 were observed for Guillain-Barré syndrome (2.49, 95 % CI: 2.15, 2.87) and cerebral venous sinus thrombosis (3.23, 95 % CI: 2.51, 4.09) following the first dose of ChAdOx1 vaccine. Acute disseminated encephalomyelitis showed an OE ratio of 3.78 (95 % CI: 1.52, 7.78) following the first dose of mRNA-1273 vaccine. The OE ratios for myocarditis and pericarditis following BNT162b2, mRNA-1273, and ChAdOx1 were significantly increased with LBCIs > 1.5., Conclusion: This multi-country analysis confirmed pre-established safety signals for myocarditis, pericarditis, Guillain-Barré syndrome, and cerebral venous sinus thrombosis. Other potential safety signals that require further investigation were identified., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeffrey C. Kwong reports financial support was provided by Centers for Disease Control and Prevention. Naveed Z. Janjua reports financial support was provided by Centers for Disease Control and Prevention. Anders Hviid reports financial support was provided by Global Vaccine Data Network. Helen Petousis-Harris reports financial support was provided by New Zealand Ministry of Health. Steven Black reports a relationship with GSK that includes: consulting or advisory. Jeffrey C. Kwong reports a relationship with Canadian Institutes of Health Research that includes: funding grants. Jeffrey C. Kwong reports a relationship with Public Health Agency of Canada that includes: funding grants. Naveed Z. Janjua reports a relationship with AbbVie Inc that includes: consulting or advisory and speaking and lecture fees. Naveed Z. Janjua reports a relationship with Gilead Sciences Inc that includes: speaking and lecture fees. Anders Hviid reports a relationship with Independent Research Fund Denmark that includes: funding grants. Anders Hviid reports a relationship with Lundbeck Foundation that includes: funding grants. Anders Hviid reports a relationship with Novo Nordisk Foundation that includes: funding grants. Anders Hviid reports a relationship with VAC4EU that includes: consulting or advisory. Finnish Institute for Health and Welfare (THL) conducts Public-Private Partnership with vaccine manufacturers and has received research funding from Sanofi Inc. Petteri Hovi has been an investigator in these studies, but has received no personal remuneration. Helen Petousis-Harris has served on expert advisory boards and had speaking engagements for Pfizer and GSK. She has also received research funding from GSK. She has not received any personal honoraria. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Vaccines developed for hepatitis B and human papilloma virus infections have been very successful in reducing the burden of cancer due to these infections. In the past decade, our understanding of the immunology of cancer has greatly improved and important progress has been made in the use of immunotherapy for several cancers. However, for the majority of cancers, an infectious etiology is either unknown or does not exist. Prostate cancer, for which no infectious etiology is known, is the most common cancer in men in the United States. Here we discuss the rationale for developing a preventive vaccine for prostate cancer, discuss a possible approach for further work in this area and a means of testing the effectiveness of a prostate cancer prevention vaccine in a clinical trial., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Vaccination is one of the most important public health tools in the prevention of infectious diseases, and in preserving life and health. While vaccines are generally safe and usually produce only transient side effects, other types of vaccine-associated adverse events do occur. Some of these reactions are immediate and easily observable or measurable, such as swelling at the injection site or a transient fever. Others however are not immediately obvious, or are even clinically "silent" or cryptic, making them challenging to identify and link directly to a vaccine. It is critical to be vigilant about rare, silent, or subtle reactions. Public health agencies and healthcare providers can play a much more favorable and vital role in establishing vaccine trust by enlarging the current vaccine safety paradigm, and in publishing and communicating, in full, these risks and benefits transparently to the public. While there are challenges in collecting and studying cryptic adverse events characterized by subjective symptoms without biomarkers, rigorous pharmacovigilance, continued research, and high-quality study designs can assist in better understanding and addressing these concerns - and in building public trust about vaccines and vaccine safety surveillance completeness., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Steven Black is a consultant for GSK on program planning and also to CEPI regarding vaccine safety. Dr. Greg Poland Dr. Poland is the chair of a Safety Evaluation Committee for novel investigational vaccine trials being conducted by Merck Research Laboratories. Dr. Poland provides consultative advice to AiZtech; Atria; GlaxoSmithKline; Invivyd; Janssen Global Services, LLC; Merck & Co. Inc.; Moderna; Novavax; Pfizer, Syneos Health; and Valneva. These activities have been reviewed by the Mayo Clinic Conflict of Interest Review Board and are conducted in compliance with Mayo Clinic Conflict of Interest policies. Dr. Poland holds patents related to vaccinia, influenza, and measles peptide vaccines. Dr. Poland has received grant funding from ICW Ventures for preclinical studies on a peptide-based COVID-19 vaccine. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies. Dr. Poland is an adviser to the White House and World Health Organization on COVID-19 vaccines and monkeypox, respectively., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The Global COVID Vaccine Safety (GCoVS) project was established in 2021 under the multinational Global Vaccine Data Network (GVDN) consortium to facilitate the rapid assessment of the safety of newly introduced vaccines. This study analyzed data from GVDN member sites on the background incidence rates of conditions designated as adverse events of special interest (AESI) for COVID-19 vaccine safety monitoring., Methods: Eleven GVDN global sites obtained data from national or regional healthcare databases using standardized methods. Incident events of 13 pre-defined AESI were included for a pre-pandemic period (2015-19) and the first pandemic year (2020). Background incidence rates (IR) and 95% confidence intervals (CI) were calculated for inpatient and emergency department encounters, stratified by age and sex, and compared between pre-pandemic and pandemic periods using incidence rate ratios., Results: An estimated 197 million people contributed 1,189,652,926 person-years of follow-up time. Among inpatients in the pre-pandemic period (2015-19), generalized seizures were the most common neurological AESI (IR ranged from 22.15 [95% CI 19.01-25.65] to 278.82 [278.20-279.44] per 100,000 person-years); acute disseminated encephalomyelitis was the least common (<0.5 per 100,000 person-years at most sites). Pulmonary embolism was the most common thrombotic event (IR 45.34 [95% CI 44.85-45.84] to 93.77 [95% CI 93.46-94.08] per 100,000 person-years). The IR of myocarditis ranged from 1.60 [(95% CI 1.45-1.76) to 7.76 (95% CI 7.46-8.08) per 100,000 person-years. The IR of several AESI varied by site, healthcare setting, age and sex. The IR of some AESI were notably different in 2020 compared to 2015-19., Conclusion: Background incidence of AESIs exhibited some variability across study sites and between pre-pandemic and pandemic periods. These findings will contribute to global vaccine safety surveillance and research., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GCoVS project reports financial support was provided by Centers for Disease Control and Prevention (CDC). Ontario site (J Kwong, S Nasreen) reports financial support was provided by Public Health Ontario and by the Institute for Clinical Evaluative Sciences (Ontario Ministry of Health). Jeffrey C Kwong reports financial support was provided by University of Toronto. Naveed Zafar Janjua reports a relationship with Gilead Sciences Inc that includes: board membership and speaking and lecture fees. Naveed Zafar Janjua reports a relationship with AbbVie Inc that includes: board membership and speaking and lecture fees. Jim Buttery reports a relationship with Vaccine Trials that includes: board membership and funding grants. Helen Petoussis Harris reports a relationship with Pharmaceutical industry that includes: board membership and funding grants. Anders Hviid reports a relationship with VAC4EU that includes: board membership., (Copyright © 2023. Published by Elsevier Ltd.)

Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Steven Black reports a relationship with GSK Vaccines SRL that includes: consulting or advisory. Stephen Evans: None.

Premature unblinding of individual participants is rarely reported in publications, but such unblinding can disrupt vaccine trials by causing worry and drop-out of other participants or "pseudo unblinding," in which participants or investigators over-interpret certain symptoms as being related to receiving an investigational product. This review summarizes appropriate reasons for unblinding in vaccine trials. Regulatory guidance could be improved by distinguishing guidance for vaccine trials from drug trials, with the recognition that unblinding individual participants in vaccine studies is rarely needed for management of adverse events following immunization., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors received support from the Coalition for Epidemic Preparedness Innovations(CEPI) either directly or through a grant administered by the Task Force for Child Survival. NH reports ongoing support from Hillevax and Takeda, and past support from Pfizer, Valneva, and Inovio for service on safety reviews or DSMBs, and support from ILiAD Biotechnologies for an advisory board. CD reports a relationship with Dynavax Technologies Corporation that includes equity or stocks and service on a Scientific Advisory Board for Medicago. MD reports current research support from Merck and previous research support from Walgreens. CW reports suppoort from Moderna Inc that includes consulting or advisory. UH reports support from Pfizer Inc, Sanofi Aventis France, InfectoPharm Medicines and Advice GmbH that includes: speaking and lecture fees, from Takeda Switzerland and HilleVax that includes consulting or advisory. KE reports support from Pfizer, Moderna, GSK, Seqirus, Merck; Roche, Sanofi for sevice on advisory committees or DSMBs and consulting fees from Bionet and X-4 Pharma.WO serves as an uncompensated member of the Moderna Scientific Advisory Board. CW reports support from Moderna. MS reports consulting, advisory, or speaking and lecture fees with Pfizer, GlaxoSmithKline, Sanofi, Merck & Co Inc, AstraZeneca Pharmaceuticals LP, Janssen Pharmaceuticals Inc and board membership with Janssen. AH, RC, JB, SE, JE, NKA,SO,YJ, NB and PP report no conflicts., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The U.S. Food and Drug Administration (FDA) Biologics Effectiveness and Safety (BEST) Initiative conducts active surveillance of adverse events of special interest (AESI) after COVID-19 vaccination. Historical incidence rates (IRs) of AESI are comparators to evaluate safety., Methods: We estimated IRs of 17 AESI in six administrative claims databases from January 1, 2019, to December 11, 2020: Medicare claims for adults ≥ 65 years and commercial claims (Blue Health Intelligence®, CVS Health, HealthCore Integrated Research Database, IBM® MarketScan® Commercial Database, Optum pre-adjudicated claims) for adults < 65 years. IRs were estimated by sex, age, race/ethnicity (Medicare), and nursing home residency (Medicare) in 2019 and for specific periods in 2020., Results: The study included >100 million enrollees annually. In 2019, rates of most AESI increased with age. However, compared with commercially insured adults, Medicare enrollees had lower IRs of anaphylaxis (11 vs 12-19 per 100,000 person-years), appendicitis (80 vs 117-155), and narcolepsy (38 vs 41-53). Rates were higher in males than females for most AESI across databases and varied by race/ethnicity and nursing home status (Medicare). Acute myocardial infarction (Medicare) and anaphylaxis (all databases) IRs varied by season. IRs of most AESI were lower during March-May 2020 compared with March-May 2019 but returned to pre-pandemic levels after May 2020. However, rates of Bell's palsy, Guillain-Barré syndrome, narcolepsy, and hemorrhagic/non-hemorrhagic stroke remained lower in multiple databases after May 2020, whereas some AESI (e.g., disseminated intravascular coagulation) exhibited higher rates after May 2020 compared with 2019., Conclusion: AESI background rates varied by database and demographics and fluctuated in March-December 2020, but most returned to pre-pandemic levels after May 2020. It is critical to standardize demographics and consider seasonal and other trends when comparing historical rates with post-vaccination AESI rates in the same database to evaluate COVID-19 vaccine safety., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Shayan Hobbi reports financial support was provided by US Food and Drug Administration, Timothy A Burrell reports financial support was provided by US Food and Drug Administration. Timothy A Burrell reports a relationship with IBM that includes: employment, Dr. Edwards has disclosed the following financial relationships. Grant Recipient from CDC (Vaccine Safety with COVID vaccines) Grant Recipient from NIH (Mentoring young investigators in vaccine sciences) Consultant from BioNet (pertussis vaccines) Consultant from IBM (vaccine safety networks) Consultant from Data safety and Monitoring Boards: Sanofi, X-4 Pharma, Seqirus, Moderna, Pfizer, Merck, GSK, Roche, Dr. Black has disclosed the following financial relationships: I am a consultant for CEPI through the SPEAC project and also a consultant for GSK on meeting planning, Djeneba Audrey Djibo reports financial support was provided by US Food and Drug Administration. Djeneba Audrey Djibo reports a relationship with CVS Health that includes: employment and equity or stocks, Daniel C. Beachler reports a relationship with Elevance Health Inc. that includes: employment and equity or stocks, Patricia Lloyd, Deborah Thompson, Rositsa Dimova, Joyce Obidi, Steve Anderson, Richard Forshee, Hui-Lee Wong, Azadeh Shoaibi, Cheryl N McMahill-Walraven reports financial support was provided by US Food and Drug Administration. Cheryl N McMahill-Walraven reports a relationship with CVS Health that includes: employment, John D. Seeger reports financial support was provided by Optum Inc. John D. Seeger reports a relationship with Optum that includes: employment and equity or stocks, Kandace Amend reports financial support was provided by Optum Inc. Kandace Amend reports a relationship with Optum that includes: employment and equity or stocks, Thomas MaCurdy reports financial support was provided by Acumen LLC. Thomas MaCurdy reports a relationship with Acumen LLC that includes: employment and equity or stocks]. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: In 2010, a safety signal was detected for narcolepsy following vaccination with Pandemrix, an AS03-adjuvanted monovalent pandemic H1N1 influenza (pH1N1) vaccine. To further assess a possible association and inform policy on future use of adjuvants, we conducted a multi-country study of narcolepsy and adjuvanted pH1N1 vaccines., Methods: We used electronic health databases to conduct a dynamic retrospective cohort study to assess narcolepsy incidence rates (IR) before and during pH1N1 virus circulation, and after pH1N1 vaccination campaigns in Canada, Denmark, Spain, Sweden, Taiwan, the Netherlands, and the United Kingdom. Using a case-control study design, we evaluated the risk of narcolepsy following AS03- and MF59-adjuvanted pH1N1 vaccines in Argentina, Canada, Spain, Switzerland, Taiwan, and the Netherlands. In the Netherlands, we also conducted a case-coverage study in children born between 2004 and 2009., Results: No changes in narcolepsy IRs were observed in any periods in single study sites except Sweden and Taiwan; in Taiwan incidence increased after wild-type pH1N1 virus circulation and in Sweden (a previously identified signaling country), incidence increased after the start of pH1N1 vaccination. No association was observed for Arepanrix-AS03 or Focetria-MF59 adjuvanted pH1N1 vaccines and narcolepsy in children or adults in the case-control study nor for children born between 2004 and 2009 in the Netherlands case-coverage study for Pandemrix-AS03., Conclusions: Other than elevated narcolepsy IRs in the period after vaccination campaigns in Sweden, we did not find an association between AS03- or MF59-adjuvanted pH1N1 vaccines and narcolepsy in children or adults in the sites studied, although power to evaluate the AS03-adjuvanted Pandemrix brand vaccine was limited in our study., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

New vaccines designed to prevent diseases endemic in low and middle-income countries (LMICs) are now being introduced without prior record of utilization in countries with robust pharmacovigilance systems. To address this deficit, our objective was to demonstrate feasibility of an international hospital-based network for the assessment of potential epidemiological associations between serious and rare adverse events and vaccines in any setting. This was done through a proof-of-concept evaluation of the risk of immune thrombocytopenic purpura (ITP) and aseptic meningitis (AM) following administration of the first dose of measles-mumps-containing vaccines using the self-controlled risk interval method in the primary analysis. The World Health Organization (WHO) selected 26 sentinel sites (49 hospitals) distributed in 16 countries of the six WHO regions. Incidence rate ratios (IRR) of 5.0 (95% CI: 2.5-9.7) for ITP following first dose of measles-containing vaccinations, and of 10.9 (95% CI: 4.2-27.8) for AM following mumps-containing vaccinations were found. The strain-specific analyses showed significantly elevated ITP risk for measles vaccines containing Schwarz (IRR: 20.7; 95% CI: 2.7-157.6), Edmonston-Zagreb (IRR: 11.1; 95% CI: 1.4-90.3), and Enders'Edmonston (IRR: 8.5; 95% CI: 1.9-38.1) strains. A significantly elevated AM risk for vaccines containing the Leningrad-Zagreb mumps strain (IRR: 10.8; 95% CI: 1.3-87.4) was also found. This proof-of-concept study has shown, for the first time, that an international hospital-based network for the investigation of rare vaccine adverse events, using common standardized procedures and with high participation of LMICs, is feasible, can produce reliable results, and has the potential to characterize differences in risk between vaccine strains. The completion of this network by adding large reference hospitals, particularly from tropical countries, and the systematic WHO-led implementation of this approach, should permit the rapid post-marketing evaluation of safety signals for serious and rare adverse events for new and existing vaccines in all settings, including LMICs., (Copyright © 2017 World Health Organization. Published by Elsevier Ltd.. All rights reserved.)

New vaccines designed to prevent diseases endemic in low and middle-income countries are being introduced without prior utilization in countries with robust vaccine pharmacovigilance systems. Our aim was to build capacity for active surveillance of vaccine adverse events in the Americas. We describe the implementation of a proof-of-concept study for the feasibility of an international collaborative hospital-based active surveillance system for vaccine safety. The study was developed and implemented in 15 sentinel sites located in seven countries of the region of the Americas, under the umbrella of the World Health Organization (WHO) Global Vaccine Safety Initiative. The study evaluated the associations between measles-mumps-rubella vaccines and two well-recognized adverse events: Immune thrombocytopenic purpura (ITP) and aseptic meningitis. The regional network contributed 63 confirmed ITP and 16 confirmed aseptic meningitis eligible cases to the global study, representing, respectively, 33% and 19% of the total cases. To ensure long-term sustainability and usefulness to investigate adverse events following new vaccine introductions in low and middle-income countries, the network needs to be strengthened with additional sites and integrated into national health systems., (Copyright © 2017 Pan American Health Organization. Published by Elsevier Ltd.. All rights reserved.)

Timely and effective evaluation of vaccine safety signals for newly developed vaccines introduced in low and middle- income countries (LMICs) is essential. The study tested the development of a global network of hospital-based sentinel sites for vaccine safety signal verification and hypothesis testing. Twenty-six sentinel sites in sixteen countries across all WHO regions participated, and 65% of the sites were from LMIC. We describe the process for the establishment and operationalization of such a network and the lessons learned in conducting a multi-country collaborative initiative. 24 out of the 26 sites successfully contributed data for the global analysis using standardised tools and procedures. Our study successfully confirmed the well-known risk estimates for the outcomes of interest. The main challenges faced by investigators were lack of adequate information in the medical records for case ascertainment and classification, and access to immunization data. The results suggest that sentinel hospitals intending to participate in vaccine safety studies strengthen their systems for discharge diagnosis coding, medical records and linkage to vaccination data. Our study confirms that a multi-country hospital-based network initiative for vaccine safety monitoring is feasible and demonstrates the validity and utility of large collaborative international studies to monitor the safety of new vaccines introduced in LMICs., (Copyright © 2017. Published by Elsevier Ltd.)

Pneumococcal conjugate vaccines have proven highly effective in decreasing invasive disease and pneumonia in young children. However, there is considerable geographic variability in the impact of these vaccines on other disease endpoints and in other age groups. Investigation of the possible causes of this variability would greatly improve our understanding of pneumococcal pathophysiology and stimulate the effort to design more broadly effective vaccines., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Immunization in pregnancy provides a promising contribution to globally reducing neonatal and under-five childhood mortality and morbidity. Thorough assessment of benefits and risks for the primarily healthy pregnant women and their unborn babies is required. The GAIA project was formed in response to the call of the World Health Organization for a globally concerted approach to actively monitor the safety of vaccines and immunization in pregnancy programs. GAIA aims to improve the quality of outcome data from clinical vaccine trials in pregnant women with a specific focus on the needs and requirements for safety monitoring in LMIC. In the first year of the project, a large and functional network of experts was created. The first outputs include a guidance document for clinical trials of immunization in pregnancy, a basic data collection guide, ten case definitions of key obstetric and neonatal health outcomes, an ontology of key terms and a map of pertinent disease codes. The GAIA Network is designed as an open and growing forum for professionals sharing the GAIA vision and aim. Based on the initial achievements, tools and services are developed to support investigators and strengthen immunization in pregnancy programs with specific focus on LMIC., (Copyright © 2016. Published by Elsevier Ltd.)

Vaccination in pregnancy is an effective strategy to prevent serious infections in mothers and their infants. Safety of this strategy is of principal importance to all stakeholders. As the number of studies assessing safety of vaccines in pregnancy increases, the need to ensure consistent collection and reporting of critical data to allow comparisons and data pooling becomes more important. The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project aims to improve data collection and create a shared understanding of maternal, fetal and neonatal outcomes in order to progress the global agenda for vaccination in pregnancy. The guidance in this document has been developed to harmonize the data collected in case report forms used for safety monitoring in clinical trials of vaccination in pregnant women. Data to be collected is prioritized to allow applicability in diverse research settings, including low and middle-income countries. Standardized data will enable the research community to have a common base upon which to conduct meta-analyses, strengthening the applicability of outcomes to different settings., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Recently an investigational meningococcal B vaccine has been used in two college outbreaks in the US. This is the first time that a meningococcal B vaccine has been used for outbreak control in the US. However, strain specific vaccines for meningococcal B outbreaks have been developed in Norway, Cuba and to control a large prolonged outbreak in New Zealand. Although meningococcal disease is mostly endemic and baseline rates in the US have fallen over the past decade, outbreaks are not uncommon in the US and globally. In an outbreak, disease risk can rise 1000 fold or more and such outbreaks can last a decade or longer causing significant morbidity and mortality. Here we review the evolution of several serogroup B outbreaks, and, when applicable, the development and impact of meningococcal B vaccines to control these outbreaks. Prior to the availability of "broad spectrum" meningococcal B vaccines, vaccines developed to control meningococcal B outbreaks were strain specific. With the development of two newly licensed meningococcal B vaccines - a four component meningococcal B vaccine (Bexsero, Novartis) and the two component fHBP vaccine (Trumenba, Pfizer) that target a broad array of meningococcal B strains, there is now the potential to prevent outbreaks and as well as to shorten the delay between identification of an outbreak and availability of a vaccine., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Maternal immunization is an effective intervention to protect newborns and young infants from infections when their immune response is immature. Tetanus toxoid vaccination of pregnant women is the most widely implemented maternal vaccine in developing countries where neonatal mortality is the highest. We identified barriers to maternal tetanus vaccination in developing African and Asian countries to identify means of improving maternal immunization platforms in these countries., Method: We categorized barriers into health system, health care provider and patient barriers to maternal tetanus immunization and conducted a literature review on each category. Due to limited literature from Africa, we conducted a pilot survey of health care providers in Malawi on barriers they experience in immunizing pregnant women., Results: The major barriers of the health system are due to inadequate financial and human resources which translate to inadequate vaccination services delivery and logistics management. Health care providers are limited by poor attendance of Antenatal Care and inadequate knowledge on vaccinating pregnant women. Patient barriers are due to lack of education and knowledge on pregnancy immunization and socioeconomic factors such as low income and high parity., Conclusion: There are several factors that affect maternal tetanus immunization. Increasing knowledge in health care providers and patients, increasing antenatal care attendance and outreach activities will aid the uptake of maternal immunization. Health system barriers are more difficult to address requiring an improvement of overall immunization services. Further analyses of maternal immunization specific barriers and the means of addressing them are required to strengthen the existing program and provide a more efficient delivery system for additional maternal vaccines., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The squalene oil-in-water emulsion MF-59 adjuvant was developed initially to enhance the immunogenicity of influenza vaccines in populations such as children and adults with known suboptimal response. Developed in the 1990s, it was initially licensed in Europe for use in seasonal influenza vaccine in the elderly. Since that time, both Avian and p2009H1N1 vaccines have also been developed. Overall, more than 30,000 individuals have participated in clinical trials of MF-59 adjuvanted vaccine and more than 160 million doses of licensed vaccine have been administered. Safety and effectiveness data from clinical trials and observation studies attest to the safety of MF-59 and to its ability to enhance the effectiveness of influenza vaccines in children and the elderly., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Beginning in the 20th century with the consideration of the seven-valent pneumococcal conjugate vaccine in the US, the cost effectiveness became a topic of discussion when this vaccine was being considered for universal use by the US Advisory Committee on Immunization practices (ACIP). In 2008, the ACIP began using formal criteria for the presentation of such data and their inclusion in ACIP discussions. More recently, the US Institute of Medicine has recommended that health economic considerations play a primary role in the prioritization of future vaccine for development. However, such analyses can be biased towards vaccines that provide economic benefit rather than those that reduce severe morbidity and mortality. This is because the economic impact of minor common events that result in medical utilization or time lost from work for parents can outweigh the economic impact of severe morbidity and mortality. Thus diseases with a low mortality and morbidity but with a common clinical manifestation such as the common cold could be prioritized over vaccines against diseases such as meningococcal sepsis where the morbidity and mortality associated with each case is very high, but there is no associated common clinical syndrome. Thus the use of cost effectiveness analyses as a 'gating criteria' to decide which vaccines should be developed or routinely used runs the risk of transforming vaccines into primarily a tool for achieving cost savings within the health care system rather than a public health intervention targeting human suffering, death and disability. It is the purpose of this article to review the framework under which health economic evaluations can be undertaken, to review the experience with and reliability of such analyses, and to discuss the potential negative implications of the use of health economic analyses as a primary decision making tool., (Copyright © 2013 The Author. Published by Elsevier Ltd.. All rights reserved.)

Background: The global spread of the 2009 novel pandemic influenza A (H1N1) virus led to the accelerated production and distribution of monovalent 2009 Influenza A (H1N1) vaccines (pH1N1). This pandemic provided the opportunity to evaluate the risk of Guillain-Barré syndrome (GBS), which has been an influenza vaccine safety concern since the swine flu pandemic of 1976, using a common protocol among high and middle-income countries. The primary objective of this project was to demonstrate the feasibility and utility of global collaboration in the assessment of vaccine safety, including countries both with and without an established infrastructure for vaccine active safety surveillance. A second objective, included a priori, was to assess the risk of GBS following pH1N1 vaccination., Methods: The primary analysis used the self-controlled case series (SCCS) design to estimate the relative incidence (RI) of GBS in the 42 days following vaccination with pH1N1 vaccine in a pooled analysis across databases and in analysis using a meta-analytic approach., Results: We found a relative incidence of GBS of 2.42 (95% CI 1.58-3.72) in the 42 days following exposure to pH1N1 vaccine in analysis of pooled data and 2.09 (95% CI 1.28-3.42) using the meta-analytic approach., Conclusions: This study demonstrates that international collaboration to evaluate serious outcomes using a common protocol is feasible. The significance and consistency of our findings support a conclusion of an association between 2009 H1N1 vaccination and GBS. Given the rarity of the event the relative incidence found does not provide evidence in contradiction to international recommendations for the continued use of influenza vaccines., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Group B Streptococcus (GBS) causes pneumonia, meningitis and sepsis in neonates. The current distribution pattern of GBS serotypes in developing countries such as India, China and Brazil is not clear. In order to appropriately plan for vaccination programs to address the burden of this disease in these countries, prospective population based studies are urgently needed. In our discussions, we focused on India, China and Brazil because of the membership of our workgroup, but data on other countries are also presented here. Further studies in developing countries are needed so as to better formulate appropriate public health interventions., (Copyright © 2013. Published by Elsevier Ltd.)

With the advent of new vaccines targeted to highly endemic diseases in low- and middle-income countries (LMIC) and with the expansion of vaccine manufacturing globally, there is an urgent need to establish an infrastructure to evaluate the benefit-risk profiles of vaccines in LMIC. Fortunately the usual decade(s)-long time gap between introduction of new vaccines in high and low income countries is being significantly reduced or eliminated due to initiatives such as the Global Alliance for Vaccines and Immunizations (GAVI) and the Decade of Vaccines for the implementation of the Global Vaccine Action Plan. While hoping for more rapid disease control, this time shift may potentially add risk, unless appropriate capacity for reliable and timely evaluation of vaccine benefit-risk profiles in some LMIC's are developed with external assistance from regional or global level. An ideal vaccine safety and effectiveness monitoring system should be flexible and sustainable, able to quickly detect possible vaccine-associated events, distinguish them from programmatic errors, reliably and quickly evaluate the suspected event and its association with vaccination and, if associated, determine the benefit-risk of vaccines to inform appropriate action. Based upon the demonstrated feasibility of active surveillance in LMIC as shown by the Burkina Faso assessment of meningococcal A conjugate vaccine or that of rotavirus vaccine in Mexico and Brazil, and upon the proof of concept international GBS study, we suggest a sustainable, flexible, affordable and timely international collaborative vaccine safety monitoring approach for vaccines being newly introduced. While this paper discusses only the vaccine component, the same system could also be eventually used for monitoring drug effectiveness (including the use of substandard drugs) and drug safety., (Published by Elsevier Ltd.)

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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Unlabelled: Adverse events following immunization (AEFI) reported to the national Vaccine Adverse Event Reporting System (VAERS) represent true causally related events, as well as events that are temporally, but not necessarily causally related to vaccine., Objective: We sought to determine if the causal relationships between the vaccine and the AEFI reported to VAERS could be assessed through expert review., Design: A stratified random sample of 100 VAERS reports received in 2004 contained 13 fatal cases, 19 cases with non-fatal disabilities, 39 other serious non-fatal cases and 29 non-serious cases. Experts knowledgeable about vaccines and clinical outcomes, reviewed each VAERS report and available medical records., Main Outcome Measures: Modified World Health Organization criteria were used to classify the causal relationship between vaccines and AEFI as definite, probable, possible, unlikely or unrelated. Five independent reviewers evaluated each report. If they did not reach a majority agreement on causality after initial review, the report was discussed on a telephone conference to achieve agreement., Results: 108 AEFIs were identified in the selected 100 VAERS reports. After initial review majority agreement was achieved for 83% of the AEFI and 17% required further discussion. In the end, only 3 (3%) of the AEFI were classified as definitely causally related to vaccine received. Of the remaining AEFI 22 (20%) were classified as probably and 22 (20%) were classified as possibly related to vaccine received; a majority (53%) were classified as either unlikely or unrelated to a vaccine received., Conclusions: Using VAERS reports and additional documentation, causality could be assessed by expert review in the majority of VAERS reports. Assessment of VAERS reports identified that causality was thought to be probable or definite in less than one quarter of reports, and these were dominated by local reactions, allergic reactions, or symptoms known to be associated with the vaccine administered., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Associations between vaccinations, particularly hepatitis B, and onset of rheumatoid arthritis (RA) have been reported, but examined in few large-scale studies., Method: Onset of RA cases and dates of vaccination against hepatitis B, tetanus, and influenza were identified in a retrospective chart review of approximately 1 million Kaiser Permanente Northern California members ages 15-59 years from 1997 through 1999. In a cohort analysis, rates of new-onset RA were compared between vaccinated and unvaccinated within 90, 180, and 365 days. In a case-control analysis, rates of vaccination during exposure intervals (90, 180, 365, and 730 days) were compared between cases and controls using conditional logistic regression., Results: 378 RA cases were included in the cohort analysis; 37 additional cases were included in the case-control analysis. In the cohort analysis the relative risks of RA onset within 90, 180, or 365 days of hepatitis B vaccination were not significant (R.R.=1.44, p=0.53; R.R.=1.67, p=0.22; R.R.=1.23, p=0.59 respectively). We found a possible association between RA and influenza vaccine in the previous 180 and 365 days in the cohort analysis (R.R=1.36, p=0.03; R.R.=1.34, p=0.01 respectively), but in the case-control analysis, cases were no more likely than controls to have received any of the three vaccines., Conclusions: In this large retrospective study we found no statistically significant association between exposure to hepatitis B vaccine and onset of RA. A possible association between RA and influenza vaccination in the cohort study was not borne out in the larger case-control analysis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The declaration by the World Health Organization (WHO) that appearance of a swine-origin novel influenza virus in 2009 represented a pandemic was based on previously adopted guidelines and the new International Health Regulations. Severity of the pandemic was not part of the definition used, but it was stated to be less than severe at the time of declaration. It was necessary, when there was still uncertainty about the overall impact of the pandemic, for vaccine production to begin to have timely availability. Countries arranged to have vaccine for their populations, and WHO attempted to secure supplies for under-resourced countries. The world had been concerned that the next pandemic might be a severe one, based on the specter of avian influenza with a case fatality of up to 80% in humans. After it was clear that the 2009 pandemic was not severe, there were accusations, especially in Europe, that countries had secured vaccine supplies mainly to benefit the manufacturers. Such charges, even when refuted, may undermine public confidence in the process which assures vaccine supply and availability of vaccine for seasonal use. Production of pandemic vaccine is conditioned on the supply of seasonal influenza vaccine; it is unrealistic to expect vaccine to be available for pandemic use when none is used for seasonal influenza. This particularly applies to poorer counties. They have traditionally not recognized that influenza is a problem, although this attitude is changing. As we go forward, we need to keep in mind the global nature of the threat of influenza. Had the 2009 pandemic been more severe, demand would have been greater and poorer counties would have had little vaccine to meet their needs. Only by taking a broad view of influenza on an annual basis can vaccine supplies be ensured for all countries of the world., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We reviewed the safety of MF59-adjuvanted versus non-adjuvanted influenza vaccines in children and adolescents (aged 6 months-18 years) in an integrated analysis of all pediatric trials evaluating MF59-containing influenza vaccines completed to date (5 trials). In the MF59-adjuvanted group (n=1181) versus the non-adjuvanted group (n=545) there was no increase in the incidence of unsolicited adverse events and serious adverse events. As expected, solicited local or systemic reactions occurred more frequently in MF59-adjuvanted subjects; however, a majority of reactions were mild and transient. These data support the safety of MF59-adjuvanted influenza vaccines in the pediatric population., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Safety monitoring following new vaccine introduction includes assessment of potential new onset autoimmune diseases (AID). As knowledge regarding AID background rates is limited, we evaluated the incidence of 11 AID in Northern California Kaiser Permanente. AID cases were identified using electronic records of members aged 10-62 years from 1998 to 2004, excluding those with AID diagnoses from 1996 to 1997. Using prespecified criteria, all identified cases of rare diseases were verified by medical record review, while a sample of cases was reviewed for common diseases; incidence rates were calculated based on the proportion of confirmed cases. Overall, the incidence of AID varied from 0.8/100,000 person-years (PY) for autoimmune hemolytic anemia (AIHA) to 54.1/100,000 PY for thyroiditis. Incidence rates in increasing order were AIHA, juvenile rheumatoid arthritis, Guillain-Barre Syndrome, idiopathic thromobocytopenia purpura, transverse myelitis, systemic lupus erythematosus, uveitis, multiple sclerosis, rheumatoid arthritis, Type 1 diabetes mellitus and thyroiditis; incidence rates also varied according to age and gender. These background incidence rates should prove useful for future observational vaccine safety studies and will help guide evaluation of potential vaccine AID events following introduction of new vaccines.

Meningococcal disease incidence is highest in infants, but a significant burden of disease also occurs in children. In this Phase II, single-centre US study, 619 healthy children (2-10 years of age) received one dose of an investigational quadrivalent meningococcal CRM(197)-conjugated vaccine (MenACWY-CRM) or a licensed quadrivalent meningococcal polysaccharide vaccine (MPSV4). Immunogenicity was assessed using the serum bactericidal assay with human complement (hSBA) at 1 and 12 months post-vaccination. Local and systemic reactions were recorded for 7 days, all adverse events (AEs) for 1 month, and medically significant and serious AEs (SAEs) for 12 months post-vaccination. For all four serogroups, more MenACWY-CRM recipients achieved an hSBA titre >or=1:4 at 1 month post-vaccination (A: 82%; C: 83%; W-135: 95%; Y: 91%) compared with the group that received MPSV4 (A: 45%; C: 66%; W-135: 71%; Y: 61%); this difference persisted through to 12 months post-vaccination. Both vaccines were well tolerated. In children 2-10 years of age, MenACWY-CRM induced a higher immune response than that of MPSV4, and was well tolerated.

Annual immunization against influenza is recommended for solid organ transplant (SOT) recipients. We used Vaccine Safety Datalink data from 1995 to 2005 to assess influenza vaccination during the first full vaccination season (September-February) following transplant among 1800 kidney, liver, and heart transplant recipients at three health maintenance organizations. Overall, 52% of recipients were vaccinated. Older age at transplant (age 50-64 years, OR 1.81, 95% CI 1.43-2.30; age > or =65 years, OR 1.94, 95% CI 1.39-2.69), receiving vaccination in the full season pre-transplant (OR 4.54, 95% CI 3.67-5.60), and year of transplantation were significant predictors of post-transplant vaccination. Although vaccine coverage increased during study years, SOT recipients are under-immunized against influenza. Efforts to understand barriers to vaccination and increase education of physicians managing patients while awaiting and after receipt of transplant are needed.

We estimated influenza- and respiratory syncytial virus (RSV)-associated hospitalizations by age, high-risk status and outcome, during the 1996/1997-1999/2000 respiratory seasons among adults who did not receive influenza vaccine. Using three health maintenance organization (HMO) databases and local viral surveillance data, we identified weeks when influenza and RSV were circulating and estimated influenza- and RSV-associated hospitalizations. Persons aged > or = 65 years with and without high-risk conditions had significantly increased rates of influenza-associated hospitalizations for pneumonia and influenza, and circulatory and respiratory diseases. Persons aged > or = 65 years with high-risk conditions also had significantly increased rates of influenza-associated hospitalizations for cardiac conditions (16.9 per 10,000 person periods). Relative to the influenza estimates for high-risk persons > or = 65 years, we found lower rates of RSV-associated hospitalizations for pneumonia and influenza diseases (23.4 per 10,000 person periods), cardiac diseases (4.3 per 10,000 person periods) and circulatory and respiratory diseases (44.0 per 10,000 person periods). Among low-risk persons aged 50-64 years, we did not identify significantly elevated rates of influenza- or RSV-associated hospitalizations. Excess hospitalization estimates among adults aged > or = 65 years and high-risk 50-64 year olds during the influenza season suggest that these groups should have priority for influenza vaccine during vaccine shortages.

Combination vaccines represent one solution to the problem of increased numbers of injections during single clinic visits. A combined DTaP-IPV (Infanrix-IPV) vaccine has been developed for use as a pre-school booster. Four hundred healthy children aged 4-6 years previously primed with 4 doses of DTaP vaccine (Infanrix), 3 doses of poliovirus vaccine and 1 dose of MMR vaccine were randomized to receive single doses of either the combined DTaP-IPV vaccine or separate DTaP and IPV vaccines in a Phase II trial (DTaP-IPV-047). All children also received a second dose of MMR vaccine. Immunogenicity was assessed in serum samples taken before and 1 month after booster administration. Safety was actively assessed for 42 days post-vaccination. Non-inferiority of the DTaP-IPV vaccine to separate DTaP and IPV vaccines was demonstrated for all DTaP antigen booster response rates and poliovirus geometric mean titers of antibody ratios. Post-vaccination, > or =99.4% of children in both groups had seroprotective levels of anti-diphtheria and anti-tetanus antibodies (> or =0.1IU/mL) and seroprotective anti-poliovirus antibody titers (> or =1:8). All children in both groups were seropositive for measles, mumps and rubella antibodies, with similar post-vaccination geometric mean concentrations/titers. No significant differences were observed in the incidence of solicited local or general symptoms, unsolicited symptoms and serious adverse events between the two groups. This combined DTaP-IPV appeared safe and immunogenic when given as a booster dose at 4-6 years of age. The DTaP-IPV vaccine had no negative effect on the response to co-administered MMR vaccine, making it well-suited for use as a pre-school booster.

Pneumococcal conjugate vaccine was introduced for routine use in infants and toddlers in the United States in March 2000. We report on the impact of the introduction of this vaccine on disease epidemiology in young children as well as secondary effects due to herd immunity in unvaccinated children and adults. As of March 2003, 157,471 children had received one or more doses of PNCV7, but only 24% of those less than two years of age received all four doses as a result of shortages of vaccine. During the last year of observation, no cases of vaccine serotype disease were seen in children less than one year of age compared with an incidence ranging between 51.5 and 98.2 cases/100,000 person years (16-34 cases per year) in the years before vaccine introduction. Similar reductions were seen in children less than five years of age. There was no evidence of any concomittant increase in pneumococcal disease caused by non-vaccine serotypes. High-level resistance of pneumococci to penicillin fell from a peak of 15% in year 2000 to 5% in the first half of 2003.

Objective: Better characterize and monitor adverse events following Dryvax vaccinia vaccination in civilian health care workers and other first responders., Design: Telephone interviews to ascertain adverse events experienced., Results: Eight hundred twenty-five vaccinees, including 44 in the comparison group, were interviewed. At 10 days, 71.4% reported blisters, 35.1% reported bumps at the vaccination site, 48.5% swelling, 47.3% scab, tiredness/lethargy/fatigue (43.6%), headache (34.2%), lymph node swelling/tenderness (28.5%), muscle pain (23.1%), chills (14.4%), joint pain 11.8%, and fever >100 degrees F (12.5%). The 12.5% reported missing work because of vaccine adverse events. Most adverse events were anticipated and of short duration.

There is little information on the safety of administration of a third dose of pneumococcal polysaccharide vaccine (PPV). The authors conducted a retrospective assessment of 316,995 adult members of three health maintenance organizations who had received one, two, or three PPV doses. Medical encounters associated with diagnosis codes potentially indicative of an injection site reaction in the week following a first, second, or third PPV dose were identified. These presumptive events occurred in 0.3% (911/279504) of the first PPV group, 0.7% (257/36888) of the second PPV group, and 0.5% (3/603) of the third PPV group (p>0.5 for both comparisons with the third PPV group). These findings do not suggest that a third PPV dose is associated with an increased risk of medically attended injection site reactions compared with a first or second PPV dose.

Vaccinating millions of Americans depends, in part, on short vaccination times. During two intranasal influenza vaccine trials, times for six vaccination steps were recorded for 497 children. The total of mean times for the steps was 115 s, almost half spent explaining the vaccine and intranasal delivery. Intranasal influenza vaccination time showed little variation by patient age, was comparable to reported intramuscular vaccination times, and was a small fraction of the visit time. Total family visit time decreased by 64 s if the youngest child was receiving a second dose. Alternative delivery systems (e.g., group visits) are needed to take advantage of short vaccination times.

Background: Hepatitis A is a major cause of epidemic hepatitis in the US. In pre-licensure trials, inactivated hepatitis A vaccine (HAV, VAQTA, Merck) was shown to be generally well-tolerated and effective in inducing immunity to hepatitis A infection in adults and children over 2 years of age. Following the licensure of this vaccine, we began a Phase IV safety evaluation in adults and in children over 2 years of age., Methods: Safety was assessed by comparing the rates of diagnoses in clinic, emergency and hospital utilization. From April 1997 to December 1998, rates of diagnoses within 30 days for the clinic and emergency setting and 60 days for hospitalization were compared with unexposed follow-up time in the same individuals both before receipt of vaccine and after the 60 days interval post-vaccination., Results: There were a total of approximately 2000 comparisons between the risk and "before" or "after" period. Among them, 106 were found to have statistically significant differences in rates (30 elevated, 76 lowered). Among children/adolescents (2-17 year-old), in the hospitalization category, the only statistically significant elevated risk found was "elective procedures", as compared with both "before" and "after" periods. In the outpatient visit category for children and adolescents, elevated risks were found for consultation/general medicine/exam when compared with both "before" and "after" periods, and ganglion and viral warts when compared with either "before" or "after" period. Among adults (> or =18 year-old), in the outpatient visit category, a statistically significant elevated relative risk was seen for diarrhea/gastroenteritis for both "before" and "after" periods. There were additionally 17 diagnostic categories that showed a statistically significantly elevated relative risk compared with either "before" or "after" period. Except for diarrhea/gastroenteritis, the other eight events were elevated only in one comparison (either "before" or "after"). These eight elevated relative risks might be explained by chance resulting from multiple comparison or seasonal variations. There were no serious adverse events judged by the investigator to be associated with HAV., Conclusion: In this large Phase IV evaluation of the safety of HAV, the vaccine appeared to be generally well-tolerated. These data support the continued routine use of HAV for vaccination in children and adults.

We report an evaluation of the short-term safety of a pediatric bivalent combination vaccine containing RECOMBIVAXHB and Liquid PedvaxHIB, COMVAX. Safety was assessed through identification of medical utilization; potential adverse events were identified through computerized clinical databases for deaths, hospitalizations, emergency room visits, and outpatient clinic visits. We calculated relative risks whenever there was at least one diagnosis-specific event in the risk period following vaccination and compared the rates in specific time windows following vaccination with rates at 31-60 days following vaccination and also with rates in a historical cohort of children. A total of 27,802 doses of COMVAX were administered, with 127 separate adverse event codes with statistically significant elevated risks, and 66 codes with significantly decreased risks. Most potentially serious diagnoses appeared in four major categories: "Respiratory Events"; "Gastroenteritis"; "Adverse Effect of Medicinal and Biological Substance, NOS"; and "Fever". There was no consistent pattern to indicate increased risks for serious respiratory or gastrointestinal illness. For fever, most of the findings appeared to be explained by changes in data collection or by concomitant vaccination with M-M-R(-)II. There was an increased risk for fever hospitalizations following shot 1. The total number of children hospitalized with fever was seven out of 12,468 children; all recovered fully. In this study population of 27,802 vaccine recipients, COMVAX appeared to have a favorable safety profile.

Objective: To review studies of the costs of pneumococcal disease and the cost effectiveness of pneumococcal conjugate vaccination conducted in association with the Kaiser Permanente Pneumococcal conjugate Efficacy Trial., Results: for each birth cohort of 3.8 million infants, routine pneumococcal conjugate vaccination program for healthy infants would prevent more than 12000 (78% of potential) meningitis and bacteremia cases, 53000 (69% of potential) pneumonia cases, and 1 million (8% of potential) otitis media episodes. Before accounting for vaccine costs, the vaccination program would reduce the costs of pneumococcal disease by $342 million in medical and $415 million in work-loss and other costs. Vaccination of healthy infants would result in net savings for society if the vaccine cost less than $46 per dose, and net savings for the health care payer if the vaccine cost less than $18 per dose.