Tick-Borne Encephalitis Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2023.

Tick-borne encephalitis (TBE) virus is focally endemic in parts of Europe and Asia. The virus is primarily transmitted to humans by the bites of infected: Ixodes species ticks but can also be acquired less frequently by alimentary transmission. Other rare modes of transmission include through breastfeeding, blood transfusion, solid organ transplantation, and slaughtering of viremic animals. TBE virus can cause acute neurologic disease, which usually results in hospitalization, often permanent neurologic or cognitive sequelae, and sometimes death. TBE virus infection is a risk for certain travelers and for laboratory workers who work with the virus. In August 2021, the Food and Drug Administration approved Ticovac TBE vaccine for use among persons aged ≥1 year. This report summarizes the epidemiology of and risks for infection with TBE virus, provides information on the immunogenicity and safety of TBE vaccine, and summarizes the recommendations of the Advisory Committee on Immunization Practices (ACIP) for use of TBE vaccine among U.S. travelers and laboratory workers.

Japanese Encephalitis among Adults: A Review.

Japanese encephalitis (JE) is becoming an increasingly important issue among adults. The reasons for this are multifactorial. During the past decades, new areas of Japanese encephalitis virus (JEV) transmission have occurred in several locations, most notably in a markedly expanded area of Australia during 2021-2022. When JEV enters new areas, cases in adults frequently occur. This is unlike the typical pattern in endemic areas where the burden of disease is in children because most adults are protected through natural immunity following earlier exposure to the virus. Even in endemic areas, JEV has become relatively more important in adults because improved JE control through childhood immunization programs has resulted in a substantial decrease in pediatric JE cases and thus more prominence of adult JE cases. Finally, increases in tourism to JE risk areas have resulted in more exposure of adult travelers, who are usually non-immune, to infection in JE risk areas. In this review we describe the increasing importance of JE in adults in some areas and then consider the comparative clinical presentation and severity of illness among children and adults.

Comparative frequency of specified adverse events following Vero cell culture-derived Japanese encephalitis and Vi capsular polysaccharide typhoid vaccines in U.S. military personnel, July 2011-August 2019.

Vero cell culture-derived Japanese encephalitis (JE) vaccine (JE-VC; Ixiaro) was approved in the United States in 2009. The previous JE vaccine, an inactivated mouse brain-derived vaccine, had been associated with rare, but serious, allergic and neurologic adverse events (AE). Studies and AE surveillance have supported JE-VC's safety, but one evaluation among military personnel found elevated hypersensitivity and neurologic AE rates. However, co-administration of multiple vaccines to some personnel might have affected results. We retrospectively compared rates of hypersensitivity and neurologic AEs within 28 days following vaccination of military personnel with JE-VC or parenteral Vi capsular polysaccharide typhoid vaccine administered without other vaccines from July 1, 2011, through August 31, 2019. Rates of most events were similar between the vaccines. Only delayed hypersensitivity reactions occurred more frequently following JE-VC (rate ratio: 4.2, 95 % CI 1.2-15.3; p = 0.03), but rates were low for both vaccines. These results support JE-VC's safety.

Fatal Case of Heartland Virus Disease Acquired in the Mid-Atlantic Region, United States.

Heartland virus (HRTV) disease is an emerging tickborne illness in the midwestern and southern United States. We describe a reported fatal case of HRTV infection in the Maryland and Virginia region, states not widely recognized to have human HRTV disease cases. The range of HRTV could be expanding in the United States.

Improving community coverage of Japanese encephalitis vaccination: lessons learned from a mass campaign in Battambang Province, Cambodia.

A mass Japanese encephalitis (JE) immunization campaign for children aged 9 months through 12 years was conducted in 2013 in Battambang province, western Cambodia. Vaccinators working at almost 2,000 immunization posts in approximately 800 villages provided vaccinations to almost 310,000 children using one dose of Chengdu Institute of Biological Products' live, attenuated SA14-14-2 JE vaccine (CD-JEV), achieving a coverage rate of greater than 90%. Lessons learned, in general for mass vaccination campaigns and specifically for vaccination with CD-JEV, are described. These observations will be of benefit for public health officials and to help inform planning for future campaigns for JE or other vaccine-preventable diseases in Cambodia and elsewhere.

COVID-19 Case Investigations Among Federally Quarantined Evacuees From Wuhan, China, and Exposed Personnel at a US Military Base, United States, February 5-21, 2020.

In February 2020, during the early days of the COVID-19 pandemic, 232 evacuees from Wuhan, China, were placed under federal 14-day quarantine upon arrival at a US military base in San Diego, California. We describe the monitoring of evacuees and responders for symptoms of COVID-19, case and contact investigations, infection control procedures, and lessons learned to inform future quarantine protocols for evacuated people from a hot spot resulting from a novel pathogen. Thirteen (5.6%) evacuees had COVID-19-compatible symptoms and 2 (0.9%) had laboratory-confirmed SARS-CoV-2. Two case investigations identified 43 contacts; 3 (7.0%) contacts had symptoms but tested negative for SARS-CoV-2 infection. Daily symptom and temperature screening of evacuees and enacted infection control procedures resulted in rapid case identification and isolation and no detected secondary transmission among evacuees or responders. Lessons learned highlight the challenges associated with public health response to a novel pathogen and the evolution of mitigation strategies as knowledge of the pathogen evolves.

An evaluation of adverse events following an immunization campaign with the live, attenuated SA14-14-2 Japanese encephalitis vaccine in Cambodia.

INTRODUCTION: Japanese encephalitis (JE) virus is the most common cause of vaccine-preventable encephalitis in Asia. The SA14-14-2 JE vaccine manufactured by Chengdu Institute of Biological Products has been shown to be safe and effective in clinical trials and childhood routine immunization programs. However, there are few published reports describing results of surveillance for adverse events following immunization (AEFI) when the vaccine is used in mass campaigns. We describe the results of AEFI surveillance following a 2013 vaccination campaign among almost 310,000 children aged 9 months-12 years in Battambang Province, Cambodia. METHODS: Routine AEFI surveillance was strengthened by staff training and supplemented by active hospital surveillance. An AEFI was defined as any sign, symptom, or disease temporally associated (i.e., within 4 weeks) with receipt of the vaccine, irrespective of whether it was considered related to immunization. Data were collected on standardized forms and causality assessments were conducted for serious AEFI. RESULTS: Passive and active surveillance detected 28 AEFI for an overall incidence of 9.0 AEFI per 100,000 doses administered. The most frequent events were vasovagal episodes (n = 7, 25%) and rash (n = 6, 21%), and most other events were common childhood conditions such as fever and vomiting. Three AEFI were classified as serious, including one hypersensitivity reaction and two meningoencephalitis cases. Of these, the hypersensitivity event was the only serious AEFI classified as being consistent with a causal association to immunization. CONCLUSIONS: Most reported adverse events were conditions that commonly occur after other childhood vaccinations or independently of vaccination, and in the context of careful monitoring for serious AEFI only one serious event consistent with a causal association with immunization was identified. These results support the good safety profile of the SA14-14-2 JE vaccine, and provide reassuring data as the vaccine's use expands.

Tick-borne encephalitis among US travellers, 2010-20.

BACKGROUND: Tick-borne encephalitis (TBE) is an arboviral disease that is focally endemic in parts of Europe and Asia. TBE cases among US travellers are rare, with previous reports of only six cases among civilian travellers through 2009 and nine military-related cases through 2020. A TBE vaccine was licenced in the USA in August 2021. Understanding TBE epidemiology and risks among US travellers can help with the counselling of travellers going to TBE-endemic areas. METHODS: Diagnostic testing for TBE in the USA is typically performed at the Centers for Disease Control and Prevention (CDC) because no commercial testing is available. Diagnostic testing for TBE at CDC since 2010 was reviewed. For individuals with evidence of TBE virus infection, information was gathered on demographics, clinical presentations and risk factors for infection. RESULTS: From 2010-20, six patients with TBE were identified. Cases occurred among both paediatric and adult travellers and all were male. Patients were diagnosed with meningitis (n = 2) or encephalitis (n = 4); none died. Cases had travelled to various countries in Europe or Russia. Three cases reported visiting friends or relatives. Activities reported included hiking, camping, trail running, or working outdoors, and two cases had a recognized tick bite. CONCLUSIONS: TBE cases among US travellers are uncommon, with these six cases being the only known TBE cases among civilian travellers during this 11-year period. Nonetheless, given potential disease severity, pre-travel counselling for travellers to TBE-endemic areas should include information on measures to reduce the risk for TBE and other tick-borne diseases, including possible TBE vaccine use if a traveller's itinerary puts them at higher risk for infection. Clinicians should consider the diagnosis of TBE in a patient with a neurologic or febrile illness recently returned from a TBE-endemic country, particularly if a tick bite or possible tick exposure is reported.

Frequency of Zika Virus Immunoglobulin M Antibody in Persons with West Nile Virus Infection.

West Nile virus (WNV) and Zika virus (ZIKV) are mosquito-borne viruses in the family Flaviviridae. Residents in, and travelers to, areas where the viruses are circulating are at risk for infection, and both viruses can cause an acute febrile illness. Given known cross-reactivity in flavivirus serologic assays, it is possible a patient with acute WNV infection could be misdiagnosed as having ZIKV infection if appropriate testing is not conducted. To understand how frequently persons with WNV infection have detectable cross-reactive ZIKV immunoglobulin M (IgM) antibody, we used archived serum samples from patients in the United States with recent WNV infection confirmed by a microsphere-based immunoassay test for IgM antibody and neutralizing antibody testing. Samples were tested for ZIKV IgM antibody with the Centers for Disease Control and Prevention (CDC) ZIKV IgM antibody capture enzyme-linked immunosorbent assay. Among 153 sera from patients with acute WNV infection, the ZIKV IgM antibody result was positive in 56 (37%; 95% confidence interval [CI] 29-44%) and equivocal in 28 (18%; 95% CI 13-25%). With 55% of samples having cross-reactive antibodies, it is important for health care providers to request appropriate testing based on the most likely cause of a patient's possible arboviral infection considering their clinical symptoms and signs, travel history, and place of residence. For cases where the epidemiology does not support the preliminary IgM findings, confirmatory neutralizing antibody testing should be performed. These measures will avoid an incorrect diagnosis of ZIKV infection, based on cross-reactive antibodies, in a person truly infected with WNV.

La Crosse Virus Disease in the United States, 2003-2019.

La Crosse virus (LACV) is an arthropod-borne virus that can cause a nonspecific febrile illness, meningitis, or encephalitis. We reviewed U.S. LACV surveillance data for 2003-2019, including human disease cases and nonhuman infections. Overall, 318 counties in 27 states, principally in the Great Lakes, mid-Atlantic, and southeastern regions, reported LACV activity. A total of 1,281 human LACV disease cases were reported, including 1,183 (92%) neuroinvasive disease cases. The median age of cases was 8 years (range: 1 month-95 years); 1,130 (88%) were aged < 18 years, and 754 (59%) were male. The most common clinical syndromes were encephalitis (N = 960; 75%) and meningitis (N = 219, 17%). The case fatality rate was 1% (N = 15). A median of 74 cases (range: 35-130) was reported per year. The average annual national incidence of neuroinvasive disease cases was 0.02 per 100,000 persons. West Virginia, North Carolina, Tennessee, and Ohio had the highest average annual state incidences (0.16-0.61 per 100,000), accounting for 80% (N = 1,030) of cases. No animal LACV infections were reported. Nine states reported LACV-positive mosquito pools, including three states with no reported human disease cases. La Crosse virus is the most common cause of pediatric neuroinvasive arboviral disease in the United States. However, surveillance data likely underestimate LACV disease incidence. Healthcare providers should consider LACV disease in patients, especially children, with febrile illness, meningitis, or encephalitis in areas where the virus circulates and advise their patients on ways to prevent mosquito bites.

Case Series of Laboratory-Associated Zika Virus Disease, United States, 2016-2019.

Zika virus diagnostic testing and laboratory research increased considerably when Zika virus began spreading through the Americas in 2015, increasing the risk for potential Zika virus exposure of laboratory workers and biomedical researchers. We report 4 cases of laboratory-associated Zika virus disease in the United States during 2016-2019. Of these, 2 were associated with needlestick injuries; for the other 2 cases, the route of transmission was undetermined. In laboratories in which work with Zika virus is performed, good laboratory biosafety practices must be implemented and practiced to reduce the risk for infection among laboratory personnel.

Risk Estimation of Sexual Transmission of Zika Virus-United States, 2016-2017.

BACKGROUND: Zika virus (ZIKV) can be transmitted sexually but the risk of sexual transmission remains unknown. Most evidence of sexual transmission is from partners of infected travelers returning from areas with ZIKV circulation. METHODS: We used data from the US national arboviral disease surveillance system on travel- and sexually acquired ZIKV disease cases during 2016-2017 to develop individual-level simulations for estimating risk of male-to-female, male-to-male, and female-to-male sexual transmission of ZIKV via vaginal and/or anal intercourse. We specified parametric distributions to characterize individual-level variability of parameters for ZIKV persistence and sexual behaviors. RESULTS: Using ZIKV RNA persistence in semen/vaginal fluids to approximate infectiousness duration, male-to-male transmission had the highest estimated probability (1.3% [95% confidence interval, CI, .4%-6.0%] per anal sex act), followed by male-to-female and female-to-male transmission (0.4% [95% CI, .3%-.6%] per vaginal/anal sex act and 0.1% [95% CI, 0%-.8%] per vaginal sex act, respectively). Models using viral isolation in semen vs RNA detection to approximate infectiousness duration predicted greater risk of sexual transmission. CONCLUSIONS: While likely insufficient to maintain sustained transmission, the estimated risk of ZIKV transmission through unprotected sex is not trivial and is especially important for pregnant women, as ZIKV infection can cause severe congenital disorders.

Persistence of IgM Antibodies after Vaccination with Live Attenuated Japanese Encephalitis Vaccine.

Japanese encephalitis (JE) is a vaccine-preventable, mosquito-borne disease. Substantial progress with JE control in Asia has been made during the past decade, with most endemic countries now having JE vaccination programs, commonly using live attenuated SA14-14-2 JE vaccine (trade name CD-JEV). If a child develops encephalitis during the weeks to months following CD-JEV vaccination and anti-JE virus IgM (JE IgM) antibody is detected in serum, the question arises if this is JE virus infection indicating vaccine failure, or persistent JE IgM antibody postvaccination. To better understand JE IgM seropositivity following vaccination, sera from 268 children from a previous CD-JEV study were tested by two different JE IgM assays to determine JE IgM antibody frequency on days 28, 180, and 365 postvaccination. With the CDC JE IgM antibody capture ELISA (MAC-ELISA), 110 children (41%) had JE IgM positive or equivocal results on their day 28 sample, and eight (3%) and two (1%) had positive or equivocal results on day 180 and day 365 samples, respectively. With the InBios JE Detect™ MAC-ELISA (Seattle, WA), 118 (44%) children had positive or equivocal results on day 28 sample, and three (1%) and one (0.4%) had positive or equivocal results on day 180 and day 365 samples, respectively. Our results indicate that more than 40% children vaccinated with CD-JEV can have JE IgM antibodies in their serum at 1 month postvaccination but JE IgM antibody is rare by 6 months. These data will help healthcare workers assess the likelihood that JE IgM antibodies in the serum of a child with encephalitis after vaccination are vaccine related.

Immune response at 12-23 months following a single dose of Vero cell culture-derived Japanese encephalitis (JE) vaccine in adults previously vaccinated with mouse brain-derived JE vaccine.

BACKGROUND: Japanese encephalitis (JE) virus is an important cause of neurological disease in Asia. JE vaccine is recommended for travelers with higher JE risk itineraries. Inactivated Vero cell culture-derived JE vaccine (JE-VC) is the only JE vaccine currently available in the United States. An inactivated mouse brain-derived JE vaccine (JE-MB) previously was available but production was discontinued. One JE-VC dose administered to adults previously vaccinated with ≥3 doses of JE-MB provides good short-term protection for at least one month, but data on longer-term protection are limited. We evaluated non-inferiority of the JE virus neutralizing antibody response at 12-23 months in JE-MB-vaccinated adults administered one JE-VC dose compared with JE vaccine-naïve adults administered a JE-VC two-dose primary series. METHODS: We obtained archived sera from U.S. military personnel and performed a 50% plaque reduction neutralization test for anti-JE virus neutralizing antibodies. We compared the geometric mean titer (GMT) and seroprotection rate at 12-23 months after one JE-VC dose in previously JE-MB-vaccinated personnel and after the second JE-VC dose in previously JE vaccine-naïve personnel. Non-inferiority was concluded if the lower bound of the two-sided 95% confidence interval (CI) of the GMT ratio in previously vaccinated to vaccine-naïve personnel was >1/1.5. RESULTS: The GMT in previously JE-MB-vaccinated persons was 75 (95% CI 63-90) and in previously JE vaccine-naïve persons was 12 (95% CI 11-14), and seroprotection rates were 94% (235/250) and 54% (135/250), respectively. The ratio of GMTs was 6.3 (95% CI: 5.0-7.7), satisfying the criterion for non-inferiority. CONCLUSIONS: One JE-VC dose in previously JE-MB-vaccinated military personnel provides good protection for at least 1-2 years. The benefits of administration of a single JE-VC dose in previously JE-MB-vaccinated adults include a shorter time to completion of re-vaccination before travel, a decrease in the risk of adverse events, and reduced costs.

Japanese Encephalitis Virus as Cause of Acute Encephalitis, Bhutan.

In 2011, Bhutan's Royal Centre for Disease Control began Japanese encephalitis (JE) surveillance at 5 sentinel hospitals throughout Bhutan. During 2011-2018, a total of 20 JE cases were detected, indicating JE virus causes encephalitis in Bhutan. Maintaining JE surveillance will help improve understanding of JE epidemiology in this country.

Screening for SARS-CoV-2 Infection Within a Psychiatric Hospital and Considerations for Limiting Transmission Within Residential Psychiatric Facilities - Wyoming, 2020.

In the United States, approximately 180,000 patients receive mental health services each day at approximately 4,000 inpatient and residential psychiatric facilities (1). SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), can spread rapidly within congregate residential settings (2-4), including psychiatric facilities. On April 13, 2020, two patients were transferred to Wyoming's state psychiatric hospital from a private psychiatric hospital that had confirmed COVID-19 cases among its residents and staff members (5). Although both patients were asymptomatic at the time of transfer and one had a negative test result for SARS-CoV-2 at the originating facility, they were both isolated and received testing upon arrival at the state facility. On April 16, 2020, the test results indicated that both patients had SARS-CoV-2 infection. In response, the state hospital implemented expanded COVID-19 infection prevention and control (IPC) procedures (e.g., enhanced screening, testing, and management of new patient admissions) and adapted some standard IPC measures to facilitate implementation within the psychiatric patient population (e.g., use of modified face coverings). To assess the likely effectiveness of these procedures and determine SARS-CoV-2 infection prevalence among patients and health care personnel (HCP) (6) at the state hospital, a point prevalence survey was conducted. On May 1, 2020, 18 days after the patients' arrival, 46 (61%) of 76 patients and 171 (61%) of 282 HCP had nasopharyngeal swabs collected and tested for SARS-CoV-2 RNA by reverse transcription-polymerase chain reaction. All patients and HCP who received testing had negative test results, suggesting that the hospital's expanded IPC strategies might have been effective in preventing the introduction and spread of SARS-CoV-2 infection within the facility. In congregate residential settings, prompt identification of COVID-19 cases and application of strong IPC procedures are critical to ensuring the protection of other patients and staff members. Although standard guidance exists for other congregate facilities (7) and for HCP in general (8), modifications and nonstandard solutions might be needed to account for the specific needs of psychiatric facilities, their patients, and staff members.

Investigation of Japanese encephalitis virus as a cause of acute encephalitis in southern Pakistan, April 2015-January 2018.

BACKGROUND: Japanese encephalitis (JE) occurs in fewer than 1% of JE virus (JEV) infections, often with catastrophic sequelae including death and neuropsychiatric disability. JEV transmission in Pakistan was documented in 1980s and 1990s, but recent evidence is lacking. Our objective was to investigate JEV as a cause of acute encephalitis in Pakistan. METHODS: Persons aged ≥1 month with possible JE admitted to two acute care hospitals in Karachi, Pakistan from April 2015 to January 2018 were enrolled. Cerebrospinal fluid (CSF) or serum samples were tested for JEV immunoglobulin M (IgM) using the InBios JE DetectTM assay. Positive or equivocal samples had confirmatory testing using plaque reduction neutralization tests. RESULTS: Among 227 patients, testing was performed on CSF in 174 (77%) and on serum in 53 (23%) patients. Six of eight patient samples positive or equivocal for JEV IgM had sufficient volume for confirmatory testing. One patient had evidence of recent West Nile virus (WNV) neurologic infection based on CSF testing. One patient each had recent dengue virus (DENV) infection and WNV infection based on serum results. Recent flavivirus infections were identified in two persons, one each based on CSF and serum results. Specific flaviviruses could not be identified due to serologic cross-reactivity. For the sixth person, JEV neutralizing antibodies were confirmed in CSF but there was insufficient volume for further testing. CONCLUSIONS: Hospital-based JE surveillance in Karachi, Pakistan could not confirm or exclude local JEV transmission. Nonetheless, Pakistan remains at risk for JE due to presence of the mosquito vector, amplifying hosts, and rice irrigation. Laboratory surveillance for JE should continue among persons with acute encephalitis. However, in view of serological cross-reactivity, confirmatory testing of JE IgM positive samples at a reference laboratory is essential.

Assessment of Immunoglobulin M Enzyme-Linked Immunosorbent Assay Ratios to Identify West Nile Virus and St. Louis Encephalitis Virus Infections During Concurrent Outbreaks of West Nile Virus and St. Louis Encephalitis Virus Diseases, Arizona 2015.

West Nile virus (WNV) and St. Louis encephalitis virus (SLEV) are closely related mosquito-borne flaviviruses that cause clinical disease ranging from febrile illness to encephalitis. The standard for serological diagnosis is immunoglobulin M (IgM) testing followed by confirmatory plaque reduction neutralization test (PRNT) to differentiate the infecting virus. However, the PRNT is time-consuming and requires manipulation of live virus. During concurrent WNV and SLEV outbreaks in Arizona in 2015, we assessed use of a diagnostic algorithm to simplify testing. It incorporated WNV and SLEV ratios based on positive-to-negative (P/N) values derived from the IgM antibody-capture enzyme-linked immunosorbent assay. We compared each sample's ratio-based result with the confirmed WNV or SLEV sample result indicated by PRNT or PCR testing. We analyzed data from 70 patients with 77 serum and cerebrospinal fluid samples, including 53 patients with confirmed WNV infection and 17 patients with confirmed SLEV infection. Both WNV and SLEV ratios had specificity ≥95%, indicating a high likelihood that each ratio was correctly identifying the infecting virus. The SLEV ratio sensitivity of 30% was much lower than the WNV ratio sensitivity of 91%, likely because of higher cross-reactivity of SLEV antibodies and generation of lower P/N values. The standard for serological diagnosis of WNV and SLEV infections remains IgM testing followed by PRNT. However, these results suggest the ratios could potentially be used as part of a diagnostic algorithm in outbreaks to substantially reduce the need for PRNTs.