Widespread Hepatitis A Outbreaks Associated with Person-to-Person Transmission - United States, 2016-2020.

Hepatitis A is a vaccine-preventable disease typically acquired through fecal-oral transmission. Hepatitis A virus (HAV) infection rates in the United States declined approximately 97% during 1995-2015 after the introduction and widespread pediatric use of hepatitis A vaccines (1). Since 2016, hepatitis A outbreaks have been reported in 37 states, involving approximately 44,650 cases, 27,250 hospitalizations, and 415 deaths as of September 23, 2022 (2). A report describing early outbreaks in four states during 2017 noted that most infections occurred among persons reporting injection or noninjection drug use or experiencing homelessness; this finding signaled a shift in HAV infection epidemiology from point-source outbreaks associated with contaminated food to large community outbreaks associated with person-to-person transmission (3). CDC analyzed interim data from 33 outbreak-affected states to characterize demographic, risk factor, and clinical outcome data from 37,553 outbreak-associated hepatitis A cases reported during August 1, 2016-December 31, 2020. Among persons with available risk factor or clinical outcome information, 56% reported drug use, 14% reported experiencing homelessness, and 61% had been hospitalized; 380 outbreak-associated deaths were reported. The most effective means to prevent and control hepatitis A outbreaks is through hepatitis A vaccination, particularly for persons at increased risk for HAV infection (4). The epidemiologic shifts identified during these outbreaks led to a 2019 recommendation by the Advisory Committee on Immunization Practices (ACIP) for vaccination of persons experiencing homelessness and reinforcement of existing vaccination recommendations for persons who use drugs (4). Substantial progress in the prevention and control of hepatitis A has been made; the number of outbreak-affected states has been reduced from 37 to 13 (2). Increased hepatitis A vaccination coverage, particularly through implementation of successful, nontraditional vaccination strategies among disproportionately affected populations (5), is needed to continue progress in halting current outbreaks and preventing similar outbreaks in the future.

Hepatitis vaccination adherence and completion rates and factors associated with low compliance: A claims-based analysis of U.S. adults.

Poor compliance with multi-dose vaccine schedules by adults for whom hepatitis (Hep) A and B vaccines are recommended contributes to major Hep A and B disease burdens among high-risk U.S. adults. Evidence on hepatitis vaccine series adherence, completion, timeliness of completion, and factors associated with these outcomes, is limited and not readily generalizable for U.S. adults. This retrospective, observational study examined adherence, completion, its timeliness, and the impact of sociodemographic and clinical factors on these outcomes among a large, geographically representative sample of U.S. adults. We analyzed the Optum Clinformatics SES administrative claims database (1/1/2010-6/30/2020) for recipients of 2-dose (HepA, HepB2) or 3-dose (HepB3, HepAB) hepatitis vaccines. Adherence was defined as receipt of booster doses within specified assessment periods, per label-recommended schedules. Completion (receipt of all doses) was assessed at 6, 12, 18, and 24 months.The study included 356,828 adults ≥19 years old who were continuously enrolled in a medical benefit plan for one (HepB2), six (HepB3; HepAB), or 18 months (HepA) prior to and following the index date (first observed vaccine dose). Adherence and 24-month completion rates were: HepA (27.0%, 28.4%), HepB2 (32.2%, 44.8%), HepB3 (14.3%, 37.3%), HepAB, (15.3%, 33.8%). Kaplan-Meier completion curves plateaued after about 6 months for HepB2 and about 12 months for HepA, HepB3, and HepAB vaccines. Logistic regression analyses showed risk for low adherence/completion was generally associated with male gender, younger age, Black or Hispanic race/ethnicity, lower educational or household income attainment, and more comorbidities. Adherence and completion rates for all hepatitis vaccine series are low, especially for males, younger adults, those with lower socio-economic status and more comorbidities. To our knowledge, this is the largest claims-based analysis of adherence and completion rates for U.S. adults initiating all currently available HepA and HepB vaccines. Findings may inform hepatitis vaccination programming.

Hepatitis A.

Hepatitis A is a common viral infection worldwide that is transmitted via the fecal-oral route. The incidence of infection in the United States decreased by more than 90% after an effective vaccine was introduced, but the number of cases has been increasing because of large community outbreaks in unimmunized individuals. Classic symptoms include fever, malaise, dark urine, and jaundice and are more common in older children and adults. People are most infectious 14 days before and seven days after the development of jaundice. Diagnosis of acute infection requires the use of serologic testing for immunoglobulin M anti-hepatitis A antibodies. The disease is usually self-limited, supportive care is often sufficient for treatment, and chronic infection or chronic liver disease does not occur. Routine hepatitis A immunization is recommended in children 12 to 23 months of age. Immunization is also recommended for individuals at high risk of contracting the infection, such as persons who use illegal drugs, those who travel to areas endemic for hepatitis A, incarcerated populations, and persons at high risk of complications from hepatitis A, such as those with chronic liver disease or HIV infection. The vaccine is usually recommended for pre- and postexposure prophylaxis, but immune globulin can be used in patients who are too young to be vaccinated or if the vaccine is contraindicated.

Evidence of Circulation of Several HAV Genetic Variants and Emergence of Potential Antigenic Variants in an Endemo-Epidemic Country before Vaccine Introduction.

Similar to several other countries in the world, the epidemiology of hepatitis A virus changed from high to intermediate endemicity level in Tunisia, which led to the occurrence of outbreaks. This study aimed to determine the genetic and antigenic variability of HAV strains circulating in Tunisia during the last few years. Genotyping using complete VP1 gene and VP1-2A junction confirmed the predominance of genotype IA, with co-circulation of several genetic and antigenic variants. Phylogenetic analysis including Tunisian and strains from other regions of the world showed the presence of at least two IA-variants within IA subgenotype. Amino-acid analysis showed several mutations in or close to epitope regions in the VP1-region. This study provides a baseline on the genetic and antigenic variability of HAV circulating strains before the introduction of vaccination into the national immunization schedule.

Hennepin County Adult Detention Center's Response to a 2019 Hepatitis A Outbreak in Minnesota.

Hennepin County Adult Detention Center (Jail) is Minnesota's largest jail. In August 2019, the Minnesota Department of Health declared a statewide hepatitis A outbreak. Within three days, Hennepin County Jail Health Services made significant changes to vaccination protocols that increased vaccination rates from 0.6% to 7.1% among detainees, who have a greater risk of contracting hepatitis A. We highlight the opportunity for jails to develop sustainable public health interventions in the setting of community outbreaks.

A randomized controlled trial of comparative effectiveness between the 2 dose and 3 dose regimens of hepatitis a vaccine in kidney transplant recipients.

Hepatitis A virus (HAV) is able to cause a spectrum of illnesses ranging from no symptom to fulminant hepatitis which may lead to acute kidney injury. Although hepatitis A vaccine is recommended in non-immune solid organ transplant recipients who live in or travel to endemic areas, the standard 2-dose vaccination regimen demonstrated less favorable immunogenicity among these population. The 3-dose regimen showed higher response rate and immune durability in patients with human immunodeficiency virus. However, this strategy has never been studied in solid organ transplant recipients. A single-center, open-labeled, computer-based randomized controlled trial (RCT) with a 2:1 allocation ratio was conducted from August 2017 to December 2018. The study compared the seroconversion rate after receiving 2- or 3-dose regimen of hepatitis A vaccine at 0, 6 and 0, 1, 6 months, respectively, in non-immune kidney transplant recipients. A total of 401 adult kidney transplant recipients were screened for anti-HAV IgG and 285 subjects had positive results so the seroprevalence was 71.1%. Of 116 seronegative recipients, 93 (80.2%) completed vaccination; 60 and 33 participants completed 2- and 3-dose vaccination, respectively. The baseline characteristics were comparable between both groups. The seroconversion rate at 1 month after vaccination was 51.7% in the standard 2-dose regimen and 48.5% in the 3-dose regimen (p = 0.769). Overall, the seroconversion rate appeared to be associated with high estimated glomerular infiltration rate, high serum albumin, and low intensity immunosuppressive regimen. Seroconversion rate after hepatitis A vaccination in kidney transplant recipients was less favorable than healthy population. Three-dose regimen did not show superior benefit over the standard 2-dose regimen. Other strategies of immunization may increase immunogenicity among kidney transplant recipients.

Hepatitis A vaccine immunogenicity 25 years after vaccination in Alaska.

The hepatitis A vaccine is recommended for all children greater than or equal to 1 year of age, however, the duration of vaccine protection is unknown and protection through adulthood is crucial to prevent symptomatic hepatitis later in life. We report on 25 years of follow-up of a cohort of Alaska Native individuals who were vaccinated in early childhood. We assessed the duration of vaccine protection by calculating the geometric mean concentration and proportion of participants with protective levels of IgG antibody to hepatitis A virus (anti-HAV) (≥20 mIU/mL) every 2 to 3 years. We estimated the amount of time until the anti-HAV dropped below protective levels using survival analyses. At 25 years, 43 of the original 144 participants were available, mean anti-HAV levels were 91.5 mIU/mL, and 35 (81.4%) had protective levels of anti-HAV. Using data from all persons and all time points, a survival analysis estimated 78.7% of participants had protective levels of anti-HAV at 25 years. The high level of protective antibodies in this cohort indicate that supplemental doses of hepatitis A vaccine are not needed 25 years after completion of the vaccine series.

Low immune response rate of HIV-infected patients to a single injection of hepatitis A vaccine.

OBJECTIVES: We aimed to evaluate the immune response of HIV-1 positive patients to a single injection of HAV vaccine in a context of vaccine shortage during the 2017 European outbreak. METHODS: We retrospectively enrolled all HIV-1 positive patients vaccinated by a single injection of HAV vaccine Vaqta 50®. HAV serology was performed before and>30 days after the vaccine injection. RESULTS: Among the 73 patients, HIV-1 viral load was≤50 copies/mL in 93.2% of the cases. Medians of CD4 and median ratio of T CD4/CD8 cells were 658/mm3 and 0.9, respectively. A low immune response rate (59.7%) was observed among the patients. Responders had a significantly higher CD4/CD8 cell ratio than non-responders. CONCLUSIONS: A serologic control should be recommended in this population in the event of a single injection vaccination schedule. During routine follow-up, and prior to any untoward event, physicians should assess the vaccination coverage of HIV-infected patients.

Factors Associated With Hepatitis A Mortality During Person-to-Person Outbreaks: A Matched Case-Control Study-United States, 2016-2019.

BACKGROUND AND AIMS: During 2016-2020, the United States experienced person-to-person hepatitis A outbreaks that are unprecedented in the vaccine era, during which case-fatality ratios reported by some jurisdictions exceeded those historically associated with hepatitis A. APPROACH AND RESULTS: To identify factors associated with hepatitis A-related mortality, we performed a matched case-control study (matched on age [±5 years] and county of residence in a 1:4 ratio) using data collected from health department and hospital medical records of outbreak-associated patients in Kentucky, Michigan, and West Virginia. Controls were hepatitis A outbreak-associated patients who did not die. There were 110 cases (mean age 53.6 years) and 414 matched controls (mean age 51.9 years); most cases (68.2%) and controls (63.8%) were male. Significantly (P < 0.05) higher odds of mortality were associated with preexisting nonviral liver disease (adjusted odds ratio [aOR], 5.2), history of hepatitis B (aOR, 2.4), diabetes (aOR, 2.2), and cardiovascular disease (aOR, 2.2), as well as initial Model for End-Stage Liver Disease (MELD) score ≥ 30 (aOR, 10.0), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio > 2 (aOR, 10.3), and platelet count < 150,000/µL (aOR, 3.7) among hepatitis A outbreak-associated patients in the independent multivariable conditional logistic regression analyses (each model adjusted for sex). CONCLUSIONS: Preexisting liver disease, diabetes, cardiovascular disease, and initial MELD score ≥ 30, AST/ALT ratio ≥ 1, and platelet count < 150,000/µL among hepatitis A patients were independently associated with higher odds of mortality. Providers should be vigilant for such features and have a low threshold to escalate care and consider consultation for liver transplantation. Our findings support the recommendation of the Advisory Committee on Immunization Practices to vaccinate persons with chronic liver disease, though future recommendations to include adults with diabetes and cardiovascular disease should be considered.

Hepatitis A epidemiology in Latin American countries: a 2020 view from a systematic literature review.

INTRODUCTION: The World Health Organization recommends vaccination against hepatitis A virus (HAV) for children aged 1 year and older in areas where endemicity has shifted from high to intermediate. There are no recent comprehensive reviews of the epidemiology of HAV infection in Latin America, but seroprevalence and socioeconomic data suggest that, with improved clean water and sanitation systems, countries are transitioning to intermediate endemicity. AREAS COVERED: We conducted a systematic literature review of the epidemiology of HAV infection in 25 countries in the Latin American region, which included gray literature. We compiled data on HAV incidence and prevalence, including the identification of epidemiological changes observed in countries that established pediatric HAV vaccination programs. EXPERT OPINION: We identified 59 relevant articles, including 34 peer-reviewed seroprevalence studies (12 recent studies from Brazil), three incidence studies, and six vaccine impact studies (three from Argentina). Based on the estimated age at midpoint of population immunity in each country, most have a high-intermediate, intermediate, or low-intermediate level of HAV endemicity, suggesting that national childhood immunization may be an appropriate disease prevention strategy. However, recent data were lacking for most countries. Improved data quality and continued epidemiological surveillance are required for this region.

Modeling the Long-term Antibody Response and Duration of Immune Protection Induced by an Inactivated, Preservative-free Hepatitis A Vaccine (Healive) in Children.

OBJECTIVE: Long-term seroprotection via the hepatitis A vaccine is essential for the prevention of disease from the hepatitis A virus (HAV). Due to documented difficulties during decade-long follow-ups after receiving vaccines, statistical-modeling approaches have been applied to predict the duration of immune protection. METHODS: Based on five-year follow-up data from a randomized positive-controlled trial among Chinese children (1-8 years old) following a 0, 6 months vaccination schedule, a power-law model accounting for the kinetics of B-cell turnover, as well as a modified power-law model considering a memory-B-cell subpopulation, were fitted to predict the long-term immune responses induced by HAV vaccination (Healive or Havrix). Anti-HAV levels of each individual and seroconversion rates up to 30 years after vaccination were predicted. RESULTS: A total of 375 participants who completed the two-dose vaccination were included in the analysis. Both models predicted that, over a life-long period, participants vaccinated with Healive would have close but slightly higher antibody titers than those of participants vaccinated with Havrix. Additionally, consistent with previous studies, more than 90% of participants were predicted to maintain seroconversion for at least 30 years. Moreover, the modified power-law model predicted that the antibody titers would reach a plateau level after nearly 15 years post-vaccination. CONCLUSIONS: Based on the results of our modeling, Healive may adequately induce long-term immune responses following a 0, 6 months vaccination schedule in children via induction of memory B cells to provide stable and durable immune protection.

Universal hepatitis A vaccination in Brazil: analysis of vaccination coverage and incidence five years after program implementation. / Vacinação universal contra hepatite A no Brasil: análise da cobertura vacinal e da incidência cinco anos após a implantação do programa.

INTRODUCTION: In 2014, Brazil introduced a universal immunization program against the hepatitis A virus (HAV) for children in the second year of life, using a single dose of inactivated virus vaccine. The objective of this study was to evaluate the vaccination coverage (VC) against HAV in Brazil, against the incidence of cases reported five years after the implementation of the program. METHODOLOGY: Secondary data were obtained by searching free access electronic sites of the Ministry of Health, Department of Informatics of the Unified Health System (Departamento de Informática do Sistema Único de Saúde - DATASUS), for incidence analysis and VC from 2014 to 2018. RESULTS: VC ranged from 60.13 to 97.07%. The homogeneity of VC against hepatitis A did not reach the established goal throughout all states but for a few exceptions. After 2015, CV decreased in all regions of the country. Despite insufficient coverage, a concomitant reduction in the incidence of Hepatitis A took place throughout the country. The incidence rate fell from 3.29 to 0.80/100,000 between 2014 and 2018. However, there was an interruption in the pace of incidence fall between 2017 and 2018, which may be a consequence of insufficient VC. This phenomenon seems to be part of a widespread downward trend in vaccination effort across the country, also verified for other vaccines, such as poliomyelitis and measles, mumps and rubella vaccine. CONCLUSION: These figures suggest the need for implementing efforts to improve hepatitis A VC rates in the country.

A previously treated severe haemophilia A patient developed high-titre inhibitor after vaccinations.

The factor VIII (FVIII)-neutralizing antibody (inhibitor) seen in 25%-30% of patients with severe haemophilia A (SHA). Vaccination is a non-genetic risk factor of inhibitor development as 'danger signal' which may provide a pro-inflammatory microenvironment to increase FVIII immunogenicity. We reported a previously treated SHA patient postponed the first vaccination to 15-month age received diphtheria-pertussis-tetanus intramuscularly. At 18-month age, the patient received Hepatitis A intramuscularly and Varicella Zoster Virus subcutaneously with 2 weeks interval and FVIII infusion was given <24 h prior for each. Successive bleedings occurred 1 week later with inefficacy of FVIII replacement. High-titre inhibitor was tested at 117 exposure days. This case suggested that continuous vaccinations in close proximity to FVIII could induce inhibitor. The relationship between vaccination and FVIII immunogenicity still needs to be revealed by further study.

Prevention of Hepatitis A Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices, 2020.

HEPATITIS A IS A VACCINE-PREVENTABLE, COMMUNICABLE DISEASE OF THE LIVER CAUSED BY THE HEPATITIS A VIRUS (HAV). THE INFECTION IS TRANSMITTED VIA THE FECAL-ORAL ROUTE, USUALLY FROM DIRECT PERSON-TO-PERSON CONTACT OR CONSUMPTION OF CONTAMINATED FOOD OR WATER. HEPATITIS A IS AN ACUTE, SELF-LIMITED DISEASE THAT DOES NOT RESULT IN CHRONIC INFECTION. HAV ANTIBODIES (IMMUNOGLOBULIN G [IGG] ANTI-HAV) PRODUCED IN RESPONSE TO HAV INFECTION PERSIST FOR LIFE AND PROTECT AGAINST REINFECTION; IGG ANTI-HAV PRODUCED AFTER VACCINATION CONFER LONG-TERM IMMUNITY. THIS REPORT SUPPLANTS AND SUMMARIZES PREVIOUSLY PUBLISHED RECOMMENDATIONS FROM THE ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES (ACIP) REGARDING THE PREVENTION OF HAV INFECTION IN THE UNITED STATES. ACIP RECOMMENDS ROUTINE VACCINATION OF CHILDREN AGED 12-23 MONTHS AND CATCH-UP VACCINATION FOR CHILDREN AND ADOLESCENTS AGED 2-18 YEARS WHO HAVE NOT PREVIOUSLY RECEIVED HEPATITIS A (HEPA) VACCINE AT ANY AGE. ACIP RECOMMENDS HEPA VACCINATION FOR ADULTS AT RISK FOR HAV INFECTION OR SEVERE DISEASE FROM HAV INFECTION AND FOR ADULTS REQUESTING PROTECTION AGAINST HAV WITHOUT ACKNOWLEDGMENT OF A RISK FACTOR. THESE RECOMMENDATIONS ALSO PROVIDE GUIDANCE FOR VACCINATION BEFORE TRAVEL, FOR POSTEXPOSURE PROPHYLAXIS, IN SETTINGS PROVIDING SERVICES TO ADULTS, AND DURING OUTBREAKS.

The Impact of Vaccination Efforts on the Spatiotemporal Patterns of the Hepatitis A Outbreak in Michigan, 2016-2018.

BACKGROUND: The United States is currently experiencing the largest hepatitis A virus (HAV) outbreak since the introduction of a vaccine in 1996. More than 31,000 cases have been reported since 2016. Although HAV had largely been considered a foodborne pathogen in recent years, this outbreak has been spread primarily through person-to-person transmission in urban settings and has been associated with homelessness and substance use. Michigan was one of the first states to report an outbreak, with 910 reported cases between August 2016 and December 2018. METHODS: We analyzed surveillance and vaccination data from Michigan using a disease transmission model to investigate how vaccine timing and coverage influenced the spatiotemporal patterns of the outbreak, distinguishing between Southeast Michigan, where the outbreak began, and the rest of the state. RESULTS: We estimated that vaccination had little impact in Southeast Michigan (3% cases averted [95% confidence interval (CI) = 1%, 8%]) but had a substantial impact in the rest of the state, preventing a larger outbreak (91% cases averted [95% CI = 85%, 97%]) lasting several more years. CONCLUSIONS: Our results emphasize the value of targeting populations where local transmission is not yet sustained rather than populations where transmission is already waning. Simulation modeling can aid in proactive rather than reactive decision-making and may help direct the response to outbreaks emerging in other states. See video abstract: http://links.lww.com/EDE/B704.

Factors associated with hepatitis A virus infection among HIV-positive patients before and after implementation of a hepatitis A virus vaccination program at a medical centre in central Taiwan.

Background Taiwan government has promoted the administration of a hepatitis A vaccine at public expense for high-risk groups as a preventive measure after the outbreak of hepatitis A virus (HAV) infections in 2015. The aim of this study was to evaluate the efficacy of such vaccination policy in patients with human immunodeficiency virus (HIV). METHODS: From January 2016 to July 2017, we enrolled 658 HIV-positive male participants. Participants were stratified into anti-HAV-positive (n = 165) and anti-HAV-negative (n = 493) groups. A total of 364 anti-HAV-negative patients received vaccination against HAV and were followed up for 1.5 years. A Cox regression model was used to estimate the effects of factors predicting positive anti-HAV detection after vaccination. RESULTS: Patients with HIV had an anti-HAV-positive prevalence of 25.1% before vaccination. Of the 364 patients inoculated with the first dose of vaccine, 58.0% received the second dose. Seroresponse rates were 50.0% and 80.6%, respectively. Antibody production was 30.0% lower in patients with a CD4 T-cell count <200 cells/µL (adjusted relative risk (ARR) = 0.7; 95% confidence interval (CI) = 0.5-0.9) compared with those with 500 cells/µL. Hepatitis C co-infection reduced the production of antibodies by 50.0% (ARR = 0.5; 95% CI = 0.2-0.8). CONCLUSION: This study suggests that vaccination against hepatitis A be administered when the immunity of an HIV-positive patient is strong. The promotion of the current vaccination policy against hepatitis A in Taiwan has improved the vaccination rate; the response rate for receiving one dose of the vaccine doubled.