Towards rabies elimination in the Asia-Pacific region: From theory to practice.

Rabies is a major neglected zoonotic disease and causes a substantial burden in the Asian region. Currently, Pacific Oceania is free of rabies but enzootic areas throughout southeast Asia represent a major risk of disease introduction to this region. On September 25-26, 2019, researchers, government officials and related stakeholders met at an IABS conference in Bangkok, Thailand to engage on the topic of human rabies mediated by dogs. The objective of the meeting was focused upon snowballing efforts towards achieving substantial progress in rabies prevention, control and elimination within Asia by 2030, and thereby to safeguard the Pacific region. Individual sessions focused upon domestic animal, wildlife and human vaccination; the production and evaluation of quality, safety and efficacy of existing rabies biologics; and the future development of new products. Participants reviewed the progress to date in eliminating canine rabies by mass vaccination, described supportive methods to parenteral administration by oral vaccine application, considered updated global and local approaches at human prophylaxis and discussed the considerable challenges ahead. Such opportunities provide continuous engagement on disease management among professionals at a trans-disciplinary level and promote new applied research collaborations in a modern One Health context.

One-week intramuscular or intradermal pre-exposure prophylaxis with human diploid cell vaccine or Vero cell rabies vaccine, followed by simulated post-exposure prophylaxis at one year: A phase III, open-label, randomized, controlled trial to assess immunogenicity and safety.

Shorter rabies pre-exposure prophylaxis (PrEP) regimens may offer improved convenience and feasibility over classic 3-week regimens, for example in regions with poor access to vaccines or for travelers to rabies-endemic regions. In this multicenter, open-label, controlled trial, 570 healthy participants aged 2-64 years were randomized to receive: 1-week PrEP (vaccination days [D]0 and 7; Group 1) or classic 3-week PrEP regimen (D0, D7, and D21; Group 2) with one 1.0 mL intramuscular [IM] dose of human diploid cell culture rabies vaccine (HDCV) at each visit; 1-week PrEP with two 0.1 mL intradermal (ID) HDCV doses at each visit (Group 3); or 1-week PrEP with one 0.5 mL IM dose (Group 4) or two 0.1 mL ID doses (Group 5) of Vero cell rabies vaccine (PVRV) at each visit. Participants received simulated post-exposure prophylactic (PEP) vaccination (two IM or ID doses of HDCV or PVRV three days apart) one year later. Rabies virus neutralizing antibody titers and seroconversion (titers ≥ 0.5 IU/mL) rates were assessed 14 days and up to 1 year post-PrEP, and pre- and post-PEP. Safety was assessed throughout the study. Seroconversion rates were high 14 days post-last PrEP injection (ranging from 96.7 % to 97.2 % across groups 1, 3-5; 1-week PrEP) and reached 100 % in Group 2 (3-week PrEP). Non-inferiority of Group 1 versus Group 2 in terms of seroconversion rates 14 days post-last PrEP injection (primary objective) was not demonstrated. After simulated PEP, all groups showed rapid and robust immune responses, with all but one participant achieving seroconversion (titers ≥ 0.5 IU/mL). There were no safety concerns, and the tolerability profiles of the vaccines were similar across the groups. A 1-week, IM or ID PrEP regimen with HDCV or PVRV provided efficacious priming, enabling rapid robust anamnestic responses to simulated PEP 1 year later across age groups. ClinicalTrials.gov number: NCT03700242. WHO Universal Trial Number (UTN): U1111-1183-5743.

Purified Vero Cell Rabies Vaccine (PVRV, Verorab®): A Systematic Review of Intradermal Use Between 1985 and 2019.

The purified Vero cell rabies vaccine (PVRV; Verorab®, Sanofi Pasteur) has been used in rabies prevention since 1985. Evolving rabies vaccination trends, including shorter intradermal (ID) regimens with reduced volume, along with WHO recommendation for ID administration has driven recent ID PVRV regimen assessments. Thus, a consolidated review comparing immunogenicity of PVRV ID regimens during pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) is timely and beneficial in identifying gaps in current research. A search of seven databases for studies published from 1985 to November 2019 identified 35 studies. PrEP was assessed in 10 studies (n = 926) with 1-3-site, 1-3-visit regimens of up to 3-months duration. Seroconversion (rabies virus neutralizing antibodies [RVNA] ≥ 0.5 IU/mL) rates of 90-100% were reported within weeks, irrespective of regimen, with robust booster responses at 1 year (100% seroconversion rates by day 14 post-booster). However, data are lacking for the current WHO-recommended, 2-site, 1-week ID PrEP regimen. PEP was assessed in 25 studies (n = 2136) across regimens of 1-week to 90-day duration. All ID PEP regimens assessed induced ≥ 99% seroconversion rates (except in HIV participants) by day 14-28. This review confirms ID PVRV suitability for rabies prophylaxis and highlights the heterogeneity of use in the field.

Single-visit, 4-site intradermal (ID) rabies vaccination induces robust immune responses 5 years after 1-week, 4-site ID primary post-exposure prophylaxis in the Philippines.

BACKGROUND: In a randomized controlled study (NCT01622062) a 1-week, 4-site intradermal (ID, 4-4-4-0-0) post-exposure prophylaxis (PEP) rabies vaccination regimen with purified Vero cell rabies vaccine (PVRV, Verorab®, Sanofi Pasteur), either without (Group 1) or with (Group 2) purified equine rabies immunoglobulin (ERIG), patients in the Philippines achieved seroconversion rates at Day 14 that were non-inferior to that of the updated Thai Red Cross (TRC) 28-day, 2-site (2-2-2-0-2) ID regimen with ERIG (Group 3). Presented here are the annual immunogenicity data up to five years after the last primary dose, and the immunogenicity and safety data following simulated PEP with single-visit, 4-site ID regimen. METHODS: Rabies virus neutralizing antibodies (RVNA) were determined by rapid fluorescent focus inhibition test (RFFIT). Participants (n = 397) received simulated PEP vaccination ID at Year 5 and RVNAs were assessed at Day 11 post-vaccination. RESULTS: Seroconversion rates (RVNA titres ≥ 0.5 IU/mL) during annual follow-up remained >95% in Group 1 and were relatively stable at 80-90% in Group 2, but decreased from 80% to 64% in Group 3. RVNA geometric mean titres (GMTs) in Group 1 were consistently higher than in the other two groups, and those in Group 3 were generally lower than in the other two groups. There was a clear anamnestic response to vaccination in all groups, with all participants achieving RVNA titres ≥ 0.5 IU/mL at Day 11 post-simulated PEP booster vaccination. There were no safety concerns raised during annual follow-up and with simulated post-exposure vaccination with PVRV. CONCLUSION: The shortened, 1-week, 4-site ID regimen with PVRV achieved persistently higher RVNA titres than the updated 2-site TRC regimen, and more participants remained seroprotected up to five years after the last dose of primary immunization. Simulated post-exposure with 4-site ID rapidly induced an anamnestic response indicative of robust protection.

Intradermal post-exposure rabies vaccination with purified Vero cell rabies vaccine: Comparison of a one-week, 4-site regimen versus updated Thai Red Cross regimen in a randomized non-inferiority trial in the Philippines.

BACKGROUND: Rabies post-exposure prophylaxis (PEP) via intradermal (ID) administration is standard practice in Asia. Accumulating evidence suggests that PEP shortened to 3 visits in one week does not adversely affect seroconversion rates or immune memory. OBJECTIVE: To determine whether the seroconversion rate at Day14 with a 1-week, 4-site (4-4-4-0-0) ID vaccination regimen with or without rabies immunoglobulin (RIG) was non-inferior to the updated Thai Red Cross (TRC) 28-day, 2-site (2-2-2-0-2) ID regimen with RIG during rabies PEP. We also assessed one-year antibody persistence. METHODS: This phase III, mono-center, open-label, randomized-controlled trial assigned participants aged ≤50 years (n = 600) exposed to suspected rabid animals and sustaining WHO Category II injuries (automatic allocation to G1) or Category III injuries (randomized to G2 or G3) to the following groups (1:1:1 ratio): G1 (n = 200), 1-week 4-site ID regimen with the purified Vero cell rabies vaccine (PVRV; Verorab®) without RIG; G2 (n = 201), 1-week 4-site ID regimen with PVRV, and purified equine rabies immunoglobulin (pERIG); G3 (n = 199), TRC 28-day, 2-site ID regimen with PVRV, and pERIG. Non-inferiority tests compared G1 vs. G3 and G2 vs. G3. Seroconversion rate was the proportion (%) of vaccinees with rabies virus neutralizing antibodies (RVNA) titers ≥0.5 IU/mL measured by rapid fluorescent focus inhibition test. RESULTS: On Day14, after the third vaccine administration, seroconversion rates were non-inferior in both comparisons and were, respectively, 100%, 99.4%, 98.8% in G1, G2, G3 with a decrease to 97.6%, 89%, 79.8% at Year 1. At Day14, RVNA geometric mean titers were 11.3 IU/mL; 9.89 IU/mL; 6.15 IU/mL, respectively, decreasing to 2.96 IU/mL, 1.37 IU/mL, 0.97 IU/mL at Year1. Safety and tolerability were similar between the three groups. CONCLUSION: The seroconversion rate at Day 14 with the 1-week 4-site ID regimen, both with and without pERIG, was non-inferior to the reference TRC 28-day 2-site ID regimen with pERIG during rabies PEP with PVRV. ClinicalTrials.gov ID: NCT01622062.

Immunogenicity and safety of a single dose of a live attenuated Japanese encephalitis chimeric virus vaccine in Vietnam: A single-arm, single-center study.

OBJECTIVE: To describe the immunogenicity and safety of the Japanese encephalitis chimeric virus vaccine (JE-CV) in children and adults in Vietnam. METHODS: In this prospective, open-label, single-center, single-arm study, 250 healthy participants aged 9 months to 60 years received a single dose of JE-CV (IMOJEV®). JE neutralizing antibody titers were assessed at baseline and 28days after vaccination using the 50% plaque reduction neutralization test (PRNT50). Safety and reactogenicity were assessed through solicited and unsolicited adverse events. FINDINGS: Seroconversion (titer ≥10 [1/dil] in participants JE seronegative [titer <10] at baseline [per protocol analysis], or a 4-fold rise from a baseline titer ≥10) and seroprotection (titer ≥10 [1/dil]) rates 28days after vaccination were both 98.5% (132/134) in the per protocol analysis, and 82.4% (201/244) and 98.8% (242/245), respectively, in the full analysis set. Geometric mean titers (GMTs) increased in all age groups from Day 0 to Day 28; Day 28/Day 0 GMT ratios were 55.3 (95% confidence interval [CI] 38.4-79.8), 348 (95% CI 211-572), 296 (95% CI 152-576) and 194 (95% CI 13.1-2870) in those aged 9 months to 4 years, 5-11 years, 12-17 years and 18-60 years, respectively, in the per protocol analysis. There were no safety concerns during the study. CONCLUSION: A single dose of JE-CV in children and adults aged 9 months to 60 years in Vietnam elicited a protective immune response and was well tolerated with no safety concerns. Registered at www.clinicaltrials.gov (NCT02492165).

Post-licensure, phase IV, safety study of a live attenuated Japanese encephalitis recombinant vaccine in children in Thailand.

BACKGROUND: Japanese encephalitis is a mosquito-borne viral disease endemic in most countries in Asia. A recombinant live, attenuated Japanese encephalitis virus vaccine, JE-CV, is licensed in 14 countries, including Thailand, for the prevention of Japanese encephalitis in adults and children. METHODS: This was a prospective, phase IV, open-label, multicentre, safety study of JE-CV conducted from November 2013 to April 2015, to evaluate rare serious adverse events (AEs). JE-CV was administered to 10,000 healthy children aged 9months to <5years in Thailand as a primary (Group 1) or booster (Group 2) vaccination. Serious AEs (SAEs), including AEs of special interest, up to 60days after administration were evaluated. Immediate Grade 3 systemic AEs up to 30min after JE-CV administration were also described. RESULTS: The median age of participants was 1.1years in Group 1 and 3.8years in Group 2. SAEs were reported in 204 (3.0%) participants in Group 1 and 59 (1.9%) participants in Group 2. Among a total of 294 SAEs in 263 participants, only three events occurring in two participants were considered related to vaccination. All three cases were moderate urticaria, none of which met the definition of AEs of special interest for hypersensitivity. AEs of special interest were reported in 28 (0.4%) participants in Group 1 and 4 (0.1%) participants in Group 2; none were considered related to vaccination. Febrile convulsion was the most frequently reported AE of special interest: 25 (0.4%) participants in Group 1; and 2 (<0.1%) in Group 2. There were no cases of Japanese encephalitis reported. No Grade 3 immediate systemic AEs were reported after any JE-CV vaccination. CONCLUSIONS: Our study did not identify any new safety concerns with JE-CV and confirms its good safety profile. This study was registered on www.clinicaltrials.gov (NCT01981967; Universal Trial Number: U1111-1127-7052).

Persistence of Rabies Virus-Neutralizing Antibodies after Vaccination of Rural Population following Vampire Bat Rabies Outbreak in Brazil.

BACKGROUND: Animal control measures in Latin America have decreased the incidence of urban human rabies transmitted by dogs and cats; currently most cases of human rabies are transmitted by bats. In 2004-2005, rabies outbreaks in populations living in rural Brazil prompted widespread vaccination of exposed and at-risk populations. More than 3,500 inhabitants of Augusto Correa (Pará State) received either post-exposure (PEP) or pre-exposure (PrEP) prophylaxis. This study evaluated the persistence of rabies virus-neutralizing antibodies (RVNA) annually for 4 years post-vaccination. The aim was to evaluate the impact of rabies PrEP and PEP in a population at risk living in a rural setting to help improve management of vampire bat exposure and provide additional data on the need for booster vaccination against rabies. METHODOLOGY/PRINCIPAL FINDINGS: This prospective study was conducted in 2007 through 2009 in a population previously vaccinated in 2005; study participants were followed-up annually. An RVNA titer >0.5 International Units (IU)/mL was chosen as the threshold of seroconversion. Participants with titers ≤0.5 IU/mL or Equivalent Units (EU)/mL at enrollment or at subsequent annual visits received booster doses of purified Vero cell rabies vaccine (PVRV). Adherence of the participants from this Amazonian community to the study protocol was excellent, with 428 of the 509 (84%) who attended the first interview in 2007 returning for the final visit in 2009. The long-term RVNA persistence was good, with 85-88.0% of the non-boosted participants evaluated at each yearly follow-up visit remaining seroconverted. Similar RVNA persistence profiles were observed in participants originally given PEP or PrEP in 2005, and the GMT of the study population remained >1 IU/mL 4 years after vaccination. At the end of the study, 51 subjects (11.9% of the interviewed population) had received at least one dose of booster since their vaccination in 2005. CONCLUSIONS/SIGNIFICANCE: This study and the events preceding it underscore the need for the health authorities in rabies enzootic countries to decide on the best strategies and timing for the introduction of routine rabies PrEP vaccination in affected areas.

Immunogenicity and Safety of a Booster Dose of a Live Attenuated Japanese Encephalitis Chimeric Vaccine Given 1 Year After Primary Immunization in Healthy Children in the Republic of Korea.

BACKGROUND: This study evaluated the effect of a booster vaccination of a new, live attenuated, Japanese encephalitis chimeric vaccine (JE-CV). Previously this vaccine has been used as a booster 12 months after priming with an inactivated vaccine and at >24 months after priming with the same JE-CV. This study evaluates the immunogenicity and safety of the JE-CV given at 12-24 months after JE-CV priming. METHODS: Phase III, open-label study in the Republic of Korea in which 119 children previously vaccinated with JE-CV at 12-24 months of age received a JE-CV booster at 12-24 months after primary vaccination. JE neutralizing antibody titers were measured using >50% plaque reduction neutralization test prebooster and 1 month postbooster vaccination. Seroprotection (SP) was defined as ≥10 (1/dil). Safety was assessed for 28 days postvaccination by parental reports. Serious adverse events were monitored for 6 months postvaccination. RESULTS: Antibody persistence was high prebooster (SP rate 93.5%). There was a strong anamnestic response postbooster vaccination, with an SP rate of 100% and a >50-fold increase in geometric mean titer from the prebooster level. Both antibody persistence and the booster response were independent of whether the booster was given at 12-17 or 18-24 months. The safety profile was good and comparable with the primary vaccination; there were no vaccine-related serious adverse events and no deaths. CONCLUSIONS: This study confirms the suitability of a JE-CV booster vaccination at 12-24 months after a primary dose of the same vaccine given at 12-24 months of age in children in the Republic of Korea.

A randomized study of the immunogenicity and safety of Japanese encephalitis chimeric virus vaccine (JE-CV) in comparison with SA14-14-2 vaccine in children in the Republic of Korea.

A new live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) has been developed based on innovative technology to give protection against JE with an improved immunogenicity and safety profile. In this phase 3, observer-blind study, 274 children aged 12-24 months were randomized 1:1 to receive one dose of JE-CV (Group JE-CV) or the SA14-14-2 vaccine currently used to vaccinate against JE in the Republic of Korea (Group SA14-14-2). JE neutralizing antibody titers were assessed using PRNT50 before and 28 days after vaccination. The primary endpoint of non-inferiority of seroconversion rates on D28 was demonstrated in the Per Protocol analysis set as the difference between Group JE-CV and Group SA14-14-2 was 0.9 percentage points (95% confidence interval [CI]: -2.35; 4.68), which was above the required -10%. Seroconversion and seroprotection rates 28 days after administration of a single vaccine dose were 100% in Group JE-CV and 99.1% in Group SA14-14-2; all children except one (Group SA14-14-2) were seroprotected. Geometric mean titers (GMTs) increased in both groups from D0 to D28; GM of titer ratios were slightly higher in Group JE-CV (182 [95% CI: 131; 251]) than Group SA14-14-2 (116 [95% CI: 85.5, 157]). A single dose of JE-CV was well tolerated and no safety concerns were identified. In conclusion, a single dose of JE-CV or SA14-14-2 vaccine elicited a comparable immune response with a good safety profile. Results obtained in healthy Korean children aged 12-24 months vaccinated with JE-CV are consistent with those obtained in previous studies conducted with JE-CV in toddlers.

Persistence of immunity from 1 year of age after one or two doses of hepatitis A vaccine given to children in Argentina.

BACKGROUND: This study was done to determine the immunogenicity of a single dose of hepatitis A vaccine in children, providing needed clinical data on the flexibility of booster administration. METHODS: Participants had received one dose of inactivated hepatitis A vaccine (Avaxim™ 80 U Pediatric) at 12-23 months of age or two doses of the same vaccine at 12 and 18 months of age prior to enrolment. Anti-hepatitis A antibody concentrations were measured at the first, second, and third year after vaccination. Suspected cases of hepatitis A in participant families were assessed and family socioeconomic data were collected. RESULTS: A series of 546 participants were enrolled. Of 467 (85.5%) participants completing 3 years of follow-up, 365 had received a single vaccine dose and 94 had received two vaccine doses. Seropositivity (anti-HAV ≥ 10 mIU/mL) at 3 years was 99.7% after one dose and 100% after two doses. At one year, geometric mean concentrations were higher after two doses (1433.9 mIU/mL, 95% confidence interval [CI] 1108-1855) than one (209.7 mIU/mL, 95% CI 190.6-230.6). Geometric mean concentrations decreased in both groups during the study, but remained well above 10 mIU/mL through the third year. The geometric mean of 3-year to one-year anti-hepatitis A concentration ratios was 0.74 (95% CI 0.70-0.79) following one dose and 0.57 (95% CI 0.47-0.70) following two doses. The greatest decrease in geometric mean concentrations occurred during the third year, ie, 21.2% in the one-dose group and 40.8% in the two-dose group. Six participants became seronegative during follow-up and responded strongly to a booster dose. Anti-hepatitis A concentrations increased in 135 children (34.9%) in the second year and 50 (13.7%) in the third year; none lived in a family with a case of hepatitis A. Three confirmed cases of hepatitis A occurred in family members. Participants belonged to a middle-income, urban/suburban population with good sanitation facilities and water supplies. CONCLUSION: A single dose of hepatitis A vaccine at 12-23 months of age resulted in hepatitis A seropositivity in all but one vaccinee after 3 years. Increased anti-hepatitis A serum concentrations suggested exposure to wild-type hepatitis A virus in this middle-class socioeconomic environment. Continuing surveillance is required to confirm the effectiveness of a single-dose hepatitis A vaccination; however, the results of the first three years are encouraging.