COVID-19 Vaccine Safety Technical (VaST) Work Group: Enhancing vaccine safety monitoring during the pandemic.

During the COVID-19 pandemic, candidate COVID-19 vaccines were being developed for potential use in the United States on an unprecedented, accelerated schedule. It was anticipated that once available, under U.S. Food and Drug Administration (FDA) Emergency Use Authorization (EUA) or FDA approval, COVID-19 vaccines would be broadly used and potentially administered to millions of individuals in a short period of time. Intensive monitoring in the post-EUA/licensure period would be necessary for timely detection and assessment of potential safety concerns. To address this, the Centers for Disease Control and Prevention (CDC) convened an Advisory Committee on Immunization Practices (ACIP) work group focused solely on COVID-19 vaccine safety, consisting of independent vaccine safety experts and representatives from federal agencies - the ACIP COVID-19 Vaccine Safety Technical Work Group (VaST). This report provides an overview of the organization and activities of VaST, summarizes data reviewed as part of the comprehensive effort to monitor vaccine safety during the COVID-19 pandemic, and highlights selected actions taken by CDC, ACIP, and FDA in response to accumulating post-authorization safety data. VaST convened regular meetings over the course of 29 months, from November 2020 through April 2023; through March 2023 FDA issued EUAs for six COVID-19 vaccines from four different manufacturers and subsequently licensed two of these COVID-19 vaccines. The independent vaccine safety experts collaborated with federal agencies to ensure timely assessment of vaccine safety data during this time. VaST worked closely with the ACIP COVID-19 Vaccines Work Group; that work group used safety data and VaST's assessments for benefit-risk assessments and guidance for COVID-19 vaccination policy. Safety topics reviewed by VaST included those identified in safety monitoring systems and other topics of scientific or public interest. VaST provided guidance to CDC's COVID-19 vaccine safety monitoring efforts, provided a forum for review of data from several U.S. government vaccine safety systems, and assured that a diverse group of scientists and clinicians, external to the federal government, promptly reviewed vaccine safety data. In the event of a future pandemic or other biological public health emergency, the VaST model could be used to strengthen vaccine safety monitoring, enhance public confidence, and increase transparency through incorporation of independent, non-government safety experts into the monitoring process, and through strong collaboration among federal and other partners.

Development of COVID-19 vaccine policy - United States, 2020-2023.

COVID-19 vaccines represent a great scientific and public health achievement in the face of overwhelming pressures from a global pandemic, preventing millions of hospitalizations and deaths due to COVID-19 vaccines in the United States. Over 675 million doses of COVID-19 vaccines have been administered in the United States, and over 80% of the U.S. population has had at least 1 dose of a COVID-19 vaccine. Over the course of the COVID-19 pandemic in the United States, over one million people died from COVID-19, and over six million were hospitalized. It has been estimated that COVID-19 vaccines prevented more than 18 million additional hospitalizations and more than 3 million additional deaths due to COVID-19 in the United States. From the beginning of the COVID-19 pandemic in 2020 through June 2023, ACIP had 35 COVID-19 focused meetings and 24 votes for COVID-19 vaccine recommendations. ACIP had the critical task of rapidly and thoroughly reviewing emerging and evolving data on COVID-19 epidemiology and vaccines, as well as making comprehensive population-based recommendations for vaccine policy and considerations for implementation through a transparent and evidence-based framework. Safe and effective COVID-19 vaccines, recommended through transparent policy discussions with ACIP, remain the best tool we have to prevent serious illness, hospitalization and death from COVID-19.

Report of the 2nd workshop of the International Collaboration on advanced vaccinology training.

At a workshop on 22-24 March 2022, leaders of 33 advanced vaccinology courses were invited to meet with partners to further the aims of the International Collaboration on Advanced Vaccinology Training (ICAVT) initiated in 2018 to assist courses in addressing challenges in priority areas and facilitate interactions and exchange of information. This included: an update to the landscape analysis of advanced vaccinology courses conducted in 2018, sharing experiences and good practices in the implementation of virtual training, reviewing the training needs of target audiences, informing courses of the principles, challenges, and added value of accreditation, discussing course evaluations and measurement of course impact, reviewing principles and support needed for quality cascade training, reviewing COVID-19 impact on training and identifying remaining related training needs, and identifying solutions to facilitate refresher courses and ways to facilitate networking of courses' alumni (particularly for virtual courses). The aims were to identify needs and impediments and implement necessary actions to facilitate sharing of information and resources between courses, to identify need for further developments of the e-Portal of the Collaboration (icavt.org) established to facilitate communication between the different courses and assist future course participants identify the most suitable course for them, and to discuss the formalization of the Collaboration. During the workshop, participants looked at several reports of surveys completed by courses and courses' alumni or partners. The COVID-19 pandemic impacted the delivery of some vaccinology courses leading to postponement, delivery online or hybrid training events. Lack of sustainable funding remained a major constraint for advanced vaccinology training and needs to be addressed. The Collaboration was consolidated with responsibilities and benefits for the members better defined. There was strong support for the Collaboration to continue with the organization of educational sessions at future workshops. The meeting re-enforced the view that there was much enthusiasm and commitment for the Global Collaboration and its core values.

Use of the Janssen (Johnson & Johnson) COVID-19 vaccine: updated interim recommendations from the advisory committee on immunization practices: United States, December 2021

On February 27, 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the adenovirus-vectored COVID-19 vaccine (Janssen Biotech, Inc., a Janssen Pharmaceutical company, Johnson & Johnson), and on February 28, 2021, the Advisory Committee on Immunization Practices (ACIP) issued an interim recommendation for its use as a single-dose primary vaccination in persons aged ≥18 years (1,2). On April 13, 2021, CDC and FDA recommended a pause in the use of Janssen COVID-19 vaccine after reports of thrombosis with thrombocytopenia syndrome (TTS), a rare condition characterized by low platelets and thrombosis, including at unusual sites such as the cerebral venous sinus (cerebral venous sinus thrombosis [CVST]), after receipt of the vaccine.* ACIP rapidly convened two emergency meetings to review reported cases of TTS, and 10 days after the pause commenced, ACIP reaffirmed its interim recommendation for use of the Janssen COVID-19 vaccine in persons aged ≥18 years, but included a warning regarding rare clotting events after vaccination, primarily among women aged 18­49 years (3). In July, after review of an updated benefit-risk assessment accounting for risks of Guillain-Barré syndrome (GBS) and TTS, ACIP concluded that benefits of vaccination with Janssen COVID-19 vaccine outweighed risks. Through ongoing safety surveillance and review of reports from the Vaccine Adverse Event Reporting System (VAERS), additional cases of TTS after receipt of Janssen COVID-19 vaccine, including deaths, were identified. On December 16, 2021, ACIP held an emergency meeting to review updated data on TTS and an updated benefit-risk assessment. At that meeting, ACIP made a recommendation for preferential use of mRNA COVID-19 vaccines over the Janssen COVID-19 vaccine, including both primary and booster doses administered to prevent COVID-19, for all persons aged ≥18 years. The Janssen COVID-19 vaccine may be considered in some situations, including for persons with a contraindication to receipt of mRNA COVID-19 vaccines. Since June 2020, ACIP has convened 23 public meetings to review data on the epidemiology of COVID-19 and the use of COVID-19 vaccines, including nine during which Janssen COVID-19 vaccine-related data were reviewed. The ACIP COVID-19 Vaccines Work Group, comprising experts in infectious diseases, vaccinology, vaccine safety, public health, and ethics, has held weekly meetings to review COVID-19 surveillance data, evidence for vaccine efficacy and safety, and implementation considerations for COVID-19 vaccines. In addition, the COVID-19 Vaccines Safety Technical Work Group (VaST), consisting of independent vaccine safety experts and established to provide expert consultation on COVID-19 vaccine safety issues, has reviewed safety data from the COVID-19 vaccination program during weekly meetings. After TTS was first identified in the United States in April 2021, a benefit-risk assessment for the use of the Janssen COVID-19 vaccine was presented to ACIP using an adapted Evidence to Recommendations (EtR) framework.† In the setting of limited COVID-19 vaccine supply in the United States at that time, ACIP reaffirmed its interim recommendations for the use of the Janssen COVID-19 vaccine in persons aged ≥18 years under FDA's EUA, which was updated to include a warning that rare clotting events might occur after vaccination, primarily among women aged 18­49 years (3). Updates to the benefit-risk assessment were also reviewed by ACIP in June 2021, after an increased risk for myocarditis, particularly in males aged 12­29 years, was observed after receipt of mRNA COVID-19 vaccines; and again, in July 2021, after an increased number of cases of GBS were identified following administration of Janssen COVID-19 vaccine (4,5). After each review, ACIP determined that the benefits of COVID-19 vaccination in preventing COVID-19 morbidity and associated mortality outweighed the risks for these rare, but serious adverse events; however, the balance of benefits and risks varied by age and sex. Ongoing postauthorization safety surveillance identified additional TTS cases and associated deaths after Janssen COVID-19 vaccination, and updated safety data were reviewed by VaST in December 2021. The COVID-19 Vaccines Work Group also reviewed an updated benefit-risk assessment of COVID-19 vaccines in the setting of new safety findings and sufficient COVID-19 vaccine supply in the United States. In addition, FDA updated the EUA fact sheets with additional TTS data in December 2021.§ A summary of the data reviewed and discussions from both VaST and the ACIP COVID-19 Vaccines Work Group were presented to ACIP during their emergency meeting on December 16, 2021.

Use of the Janssen (Johnson & Johnson) COVID-19 Vaccine: Updated Interim Recommendations from the Advisory Committee on Immunization Practices - United States, December 2021.

On February 27, 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the adenovirus-vectored COVID-19 vaccine (Janssen Biotech, Inc., a Janssen Pharmaceutical company, Johnson & Johnson), and on February 28, 2021, the Advisory Committee on Immunization Practices (ACIP) issued an interim recommendation for its use as a single-dose primary vaccination in persons aged ≥18 years (1,2). On April 13, 2021, CDC and FDA recommended a pause in the use of Janssen COVID-19 vaccine after reports of thrombosis with thrombocytopenia syndrome (TTS), a rare condition characterized by low platelets and thrombosis, including at unusual sites such as the cerebral venous sinus (cerebral venous sinus thrombosis [CVST]), after receipt of the vaccine.* ACIP rapidly convened two emergency meetings to review reported cases of TTS, and 10 days after the pause commenced, ACIP reaffirmed its interim recommendation for use of the Janssen COVID-19 vaccine in persons aged ≥18 years, but included a warning regarding rare clotting events after vaccination, primarily among women aged 18-49 years (3). In July, after review of an updated benefit-risk assessment accounting for risks of Guillain-Barré syndrome (GBS) and TTS, ACIP concluded that benefits of vaccination with Janssen COVID-19 vaccine outweighed risks. Through ongoing safety surveillance and review of reports from the Vaccine Adverse Event Reporting System (VAERS), additional cases of TTS after receipt of Janssen COVID-19 vaccine, including deaths, were identified. On December 16, 2021, ACIP held an emergency meeting to review updated data on TTS and an updated benefit-risk assessment. At that meeting, ACIP made a recommendation for preferential use of mRNA COVID-19 vaccines over the Janssen COVID-19 vaccine, including both primary and booster doses administered to prevent COVID-19, for all persons aged ≥18 years. The Janssen COVID-19 vaccine may be considered in some situations, including for persons with a contraindication to receipt of mRNA COVID-19 vaccines.

Use of COVID-19 Vaccines After Reports of Adverse Events Among Adult Recipients of Janssen (Johnson & Johnson) and mRNA COVID-19 Vaccines (Pfizer-BioNTech and Moderna): Update from the Advisory Committee on Immunization Practices - United States, July 2021.

In December 2020, the Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUAs) for Pfizer-BioNTech and Moderna COVID-19 vaccines, and in February 2021, FDA issued an EUA for the Janssen (Johnson & Johnson) COVID-19 vaccine. After each EUA, the Advisory Committee on Immunization Practices (ACIP) issued interim recommendations for vaccine use; currently Pfizer-BioNTech is authorized and recommended for persons aged ≥12 years and Moderna and Janssen for persons aged ≥18 years (1-3). Both Pfizer-BioNTech and Moderna vaccines, administered as 2-dose series, are mRNA-based COVID-19 vaccines, whereas the Janssen COVID-19 vaccine, administered as a single dose, is a recombinant replication-incompetent adenovirus-vector vaccine. As of July 22, 2021, 187 million persons in the United States had received at least 1 dose of COVID-19 vaccine (4); close monitoring of safety surveillance has demonstrated that serious adverse events after COVID-19 vaccination are rare (5,6). Three medical conditions have been reported in temporal association with receipt of COVID-19 vaccines. Two of these (thrombosis with thrombocytopenia syndrome [TTS], a rare syndrome characterized by venous or arterial thrombosis and thrombocytopenia, and Guillain-Barré syndrome [GBS], a rare autoimmune neurologic disorder characterized by ascending weakness and paralysis) have been reported after Janssen COVID-19 vaccination. One (myocarditis, cardiac inflammation) has been reported after Pfizer-BioNTech COVID-19 vaccination or Moderna COVID-19 vaccination, particularly after the second dose; these were reviewed together and will hereafter be referred to as mRNA COVID-19 vaccination. ACIP has met three times to review the data associated with these reports of serious adverse events and has comprehensively assessed the benefits and risks associated with receipt of these vaccines. During the most recent meeting in July 2021, ACIP determined that, overall, the benefits of COVID-19 vaccination in preventing COVID-19 morbidity and mortality outweigh the risks for these rare serious adverse events in adults aged ≥18 years; this balance of benefits and risks varied by age and sex. ACIP continues to recommend COVID-19 vaccination in all persons aged ≥12 years. CDC and FDA continue to closely monitor reports of serious adverse events and will present any additional data to ACIP for consideration. Information regarding risks and how they vary by age and sex and type of vaccine should be disseminated to providers, vaccine recipients, and the public.

Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients: Update from the Advisory Committee on Immunization Practices - United States, June 2021.

In December 2020, the Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUAs) for the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine and the Moderna COVID-19 (mRNA-1273) vaccine,† and the Advisory Committee on Immunization Practices (ACIP) issued interim recommendations for their use in persons aged ≥16 years and ≥18 years, respectively.§ In May 2021, FDA expanded the EUA for the Pfizer-BioNTech COVID-19 vaccine to include adolescents aged 12-15 years; ACIP recommends that all persons aged ≥12 years receive a COVID-19 vaccine. Both Pfizer-BioNTech and Moderna vaccines are mRNA vaccines encoding the stabilized prefusion spike glycoprotein of SARS-CoV-2, the virus that causes COVID-19. Both mRNA vaccines were authorized and recommended as a 2-dose schedule, with second doses administered 21 days (Pfizer-BioNTech) or 28 days (Moderna) after the first dose. After reports of myocarditis and pericarditis in mRNA vaccine recipients,¶ which predominantly occurred in young males after the second dose, an ACIP meeting was rapidly convened to review reported cases of myocarditis and pericarditis and discuss the benefits and risks of mRNA COVID-19 vaccination in the United States. Myocarditis is an inflammation of the heart muscle; if it is accompanied by pericarditis, an inflammation of the thin tissue surrounding the heart (the pericardium), it is referred to as myopericarditis. Hereafter, myocarditis is used to refer to myocarditis, pericarditis, or myopericarditis. On June 23, 2021, after reviewing available evidence including that for risks of myocarditis, ACIP determined that the benefits of using mRNA COVID-19 vaccines under the FDA's EUA clearly outweigh the risks in all populations, including adolescents and young adults. The EUA has been modified to include information on myocarditis after receipt of mRNA COVID-19 vaccines. The EUA fact sheets should be provided before vaccination; in addition, CDC has developed patient and provider education materials about the possibility of myocarditis and symptoms of concern, to ensure prompt recognition and management of myocarditis.

Vaccine safety issues at the turn of the 21st century.

Global gains in vaccination coverage during the early 21st century have been threatened by the emergence of antivaccination groups that have questioned the effectiveness of vaccines to generate public distrust of vaccines and immunisation programmes. This manuscript summarises six key topics that have been at the centre of global discussions on vaccine safety during the early 21st century: thiomersal in multi-dose non-live vaccines, aluminium adjuvants used with several non-live vaccines, autism and auto-immune conditions as possible consequences of vaccination, a risk of immune overload with increasing numbers of vaccinations, and detrimental non-specific effects (NSEs) of vaccination. For each topic, we describe the hypothesis behind the public concern, the evidence reviewed by the WHO's Global Advisory Committee for Vaccine Safety (GACVS) during 1999-2019, and any significant new data that has emerged since GACVS conclusions were made. Although the scientific evidence on these issues overwhelmingly supports the safety of vaccines, communication messages to caregivers and providers need to condense and convey scientific information in an appropriate way to address concerns contributing to vaccine distrust. In addition, there is need for further studies specifically designed to address both positive and negative NSE of vaccination. The role of GACVS will be increasingly important in evaluating the evidence and engaging the global community in promoting and assuring the safety of vaccines in the decades to come as we move into an era in which we use new vaccination platforms, antigens and formulations.

Progress in Vaccine-Preventable and Respiratory Infectious Diseases-First 10 Years of the CDC National Center for Immunization and Respiratory Diseases, 2006-2015.

The need for closer linkages between scientific and programmatic areas focused on addressing vaccine-preventable and acute respiratory infections led to establishment of the National Center for Immunization and Respiratory Diseases (NCIRD) at the Centers for Disease Control and Prevention. During its first 10 years (2006-2015), NCIRD worked with partners to improve preparedness and response to pandemic influenza and other emergent respiratory infections, provide an evidence base for addition of 7 newly recommended vaccines, and modernize vaccine distribution. Clinical tools were developed for improved conversations with parents, which helped sustain childhood immunization as a social norm. Coverage increased for vaccines to protect adolescents against pertussis, meningococcal meningitis, and human papillomavirus-associated cancers. NCIRD programs supported outbreak response for new respiratory pathogens and oversaw response of the Centers for Disease Control and Prevention to the 2009 influenza A(H1N1) pandemic. Other national public health institutes might also find closer linkages between epidemiology, laboratory, and immunization programs useful.

Contributions and challenges for worldwide vaccine safety: The Global Advisory Committee on Vaccine Safety at 15 years.

In 1999, the Global Advisory Committee on Vaccine Safety (GACVS) was established by the World Health Organization (WHO) to provide independent scientific advice on issues relating to the safety of vaccines and immunization. Fifteen years onward, we conducted a multi-faceted review to evaluate the impact, reach and challenges facing GACVS, including the role GACVS plays in informing global, regional and WHO member state vaccine policy. The methods included measures of organizational structure, citation impact, themes approached, and a discussion by previous and current members to evaluate past, present and future challenges. Given the increasing range of data sources and the deployment of many new vaccines, the Committee is facing the complex task of identifying the best available evidence for recommendations on vaccine safety. To help meet the increased demand for public transparency in decision making, GACVS-structured methodology for evidence-based decisions is evolving. GACVS also promotes best practices and capacity building for timely and accurate risk assessment; risk communications; outreach to help countries maintain and, if needed, rebuild public trust in vaccines; and advocacy for bridging the major gaps in vaccine safety capacity globally.

Multistate Outbreak of Respiratory Infections Among Unaccompanied Children, June 2014-July 2014.

BACKGROUND: From January 2014-July 2014, more than 46 000 unaccompanied children (UC) from Central America crossed the US-Mexico border. In June-July, UC aged 9-17 years in 4 shelters and 1 processing center in 4 states were hospitalized with acute respiratory illness. We conducted a multistate investigation to interrupt disease transmission. METHODS: Medical charts were abstracted for hospitalized UC. Nonhospitalized UC with influenza-like illness were interviewed, and nasopharyngeal and oropharyngeal swabs were collected to detect respiratory pathogens. Nasopharyngeal swabs were used to assess pneumococcal colonization in symptomatic and asymptomatic UC. Pneumococcal blood isolates from hospitalized UC and nasopharyngeal isolates were characterized by serotyping and whole-genome sequencing. RESULTS: Among 15 hospitalized UC, 4 (44%) of 9 tested positive for influenza viruses, and 6 (43%) of 14 with blood cultures grew pneumococcus, all serotype 5. Among 48 nonhospitalized children with influenza-like illness, 1 or more respiratory pathogens were identified in 46 (96%). Among 774 nonhospitalized UC, 185 (24%) yielded pneumococcus, and 70 (38%) were serotype 5. UC transferring through the processing center were more likely to be colonized with serotype 5 (odds ratio, 3.8; 95% confidence interval, 2.1-6.9). Analysis of core pneumococcal genomes detected 2 related, yet independent, clusters. No pneumococcus cases were reported after pneumococcal and influenza immunization campaigns. CONCLUSIONS: This respiratory disease outbreak was due to multiple pathogens, including Streptococcus pneumoniae serotype 5 and influenza viruses. Pneumococcal and influenza vaccinations prevented further transmission. Future efforts to prevent similar outbreaks will benefit from use of both vaccines.

Vaccine safety: current systems and recent findings.

PURPOSE OF REVIEW: An understanding of vaccine safety is important for all immunization providers, who have responsibilities to identify, report, and prevent adverse events. RECENT FINDINGS: New analytic methods can provide more rapid information on adverse events compared with traditional observational studies. Some adverse events following vaccination are preventable. Syncope is increasingly recognized postvaccination and may be associated with severe injury or death. Both human and system factors should be addressed to prevent vaccine administration errors. Ongoing basic science and clinical research is critical to improved understanding of vaccine safety. A recent study suggests that many cases of encephalopathy following whole-cell pertussis vaccine were due to severe myoclonic epilepsy of infancy, a severe seizure disorder associated with mutations of the sodium channel gene SCN1A. SUMMARY: Vaccine safety requires prelicensure evaluation, postlicensure surveillance and investigation, addressing preventable adverse events, reconsideration of vaccine policy as understanding of risks and benefits changes, and ongoing research to better understand the response to vaccination and the pathogenesis of adverse events.

Ischemic cardiac events during the Department of Health and Human Services Smallpox Vaccination Program, 2003.

Ten ischemic cardiac events (ICEs) were reported among 37,901 initial US Department of Health and Human Services (DHHS) smallpox vaccinees. Symptoms developed a median of 10 days after vaccination (range, 0-28 days). The median age of case patients was 56 years (range, 42-65 years), and 60% were male. Seven (70%) of the case patients had >/=3 cardiac risk factors or probable coronary artery disease before vaccination. Two women, 55 and 57 years of age, experienced acute myocardial infarction and fatal cardiac arrests. Background rates of ICEs during a 3-week period for civilian populations that were age and sex matched to DHHS vaccinees were estimated. The observed number of myocardial infarctions exceeded estimated expectations (5 vs. 2) but remained within the 95% predictive interval (PI) (0.6-5.4). New onset angina was observed significantly less frequently than estimated expectations (1 vs. 10; 95% PI, 3.5-15.7). After persons with >/=3 cardiac risk factors or known heart disease were deferred from vaccination, no ICEs were reported among an additional 6638 vaccinees.

Myocarditis, pericarditis, and dilated cardiomyopathy after smallpox vaccination among civilians in the United States, January-October 2003.

Myocarditis was reported after smallpox vaccination in Europe and Australia, but no association had been reported with the US vaccine. We conducted surveillance to describe and determine the frequency of myocarditis and/or pericarditis (myo/pericarditis) among civilians vaccinated during the US smallpox vaccination program between January and October 2003. We developed surveillance case definitions for myocarditis, pericarditis, and dilated cardiomyopathy after smallpox vaccination. We identified 21 myo/pericarditis cases among 37,901 vaccinees (5.5 per 10,000); 18 (86%) were revacinees, 14 (67%) were women, and the median age was 48 years (range, 25-70 years). The median time from vaccination to onset of symptoms was 11 days (range, 2-42 days). Myo/pericarditis severity was mild, with no fatalities, although 9 patients (43%) were hospitalized. Three additional vaccinees were found to have dilated cardiomyopathy, recognized within 3 months after vaccination. We describe an association between smallpox vaccination, using the US vaccinia strain, and myo/pericarditis among civilians.

Investigations of 2 cases of diphtheria-like illness due to toxigenic Corynebacterium ulcerans.

BACKGROUND: We present 2 case reports in the United States and investigations of diphtheria-like illness caused by toxigenic Corynebacterium ulcerans. A fatal case occurred in a 75-year-old male Washington resident who was treated with clindamycin but did not receive equine diphtheria antitoxin. A second, nonfatal case occurred in a 66-year-old female Tennessee resident who received erythromycin and diphtheria antitoxin. METHODS: Both case patients and close human and animal contacts were investigated by their respective state health departments. RESULTS: C. ulcerans isolated from the patient who died was resistant to erythromycin and clindamycin. For both isolates, conventional polymerase chain reaction results were positive for A and B subunits of diphtheria toxin gene tox, and modified Elek tests confirmed toxin production. The source of infection remained undetermined for both cases. Neither patient was up-to-date with diphtheria toxoid vaccination. CONCLUSION: These case reports highlight the importance of early treatment with diphtheria antitoxin, the selection of effective antimicrobial agents, and prevention through up-to-date vaccination.

Respiratory diphtheria among highly vaccinated military trainees in Latvia: improved protection from DT compared with Td booster vaccination.

An outbreak of respiratory diphtheria occurred among highly-vaccinated trainees at a Latvian military academy in August-September 2000. We reviewed immunization, clinical and laboratory records and administered a questionnaire to obtain data on exposure factors. Among 207 trainees, 45 (22%) diphtheria cases and 79 (38%) carriers of toxigenic Corynebacterium diphtheriae were identified. All patients survived; 1 had severe myocarditis. Sharing cups was a risk factor for infection. Over 85% of trainees had received > or =5 doses of diphtheria toxoid. Neither infection nor disease was associated with the number of doses or interval since last dose. However, the risk of disease was lower and diphtheria antitoxin levels were higher among trainees who received their last booster dose with higher-antigen diphtheria toxoid (DT) instead of lower-antigen Td. Outbreaks of mild diphtheria can occur among highly-vaccinated persons living in crowded conditions with intense exposure; high-antigen diphtheria booster-vaccination might provide better protection under these conditions.