Safety and immunogenicity of the yellow fever vaccine for patients with end-stage renal disease.

INTRODUCTION: In December 2016, an outbreak of sylvatic yellow fever (YF) occurred in the non-endemic areas of the south-eastern region of Brazil. The immune response to the yellow fever vaccine and its safety in individuals with chronic kidney disease (CKD) living in YF-endemic regions are not thoroughly understood. The objective of this study is to assess the incidence of adverse events and the serological response after primary vaccination with the 17DD-YF vaccine in CKD patients undergoing dialysis. METHODS: This was a multicenter, retrospective cohort study involving 223 individuals with CKD who were on dialysis after primary vaccination against YF. Clinical and epidemiologic characteristics were collected and the vaccine adverse event (VAE) were assessed. Around 35 months after vaccination, the serological response was evaluated in 71 (32%) patients using neutralization tests. RESULTS: No serious VAE occurred in any patient. Local reactions were reported in 13 individuals (5.8%), while 6 (2.7%) reported generalized systemic reactions and 205 (91.9%) did not display any VAE. No clinical or epidemiologic characteristic predicted the occurrence of VAE. Adequate serological response was found in 38% of participants and none of the clinical or epidemiological characteristics were associated with immunogenicity. CONCLUSION: The outcomes of our study suggest that the yellow YF vaccine is well-tolerated in CKD patients undergoing dialysis, but it does not induce adequate immune response. Future research should focus on evaluating both cellular and humoral immune responses following administration of various doses of the YF vaccine.

Adverse events following immunization (AEFI) with fractional one-fifth and one-half doses of yellow fever vaccine compared to full dose in children 9-23 months old in Uganda, 2019-2020 - Preliminary report.

BACKGROUND: In 2016, the World Health Organization recommended that a fractional dose of yellow fever (YF) vaccine could be used in persons 2 years of age or older in response to an emergency that resulted in a global shortage of available YF vaccine. However, this recommendation did not extend to the youngest age group licensed for YF vaccine because there were no published data on the use or safety of fractional dose YF vaccination in children aged 9-23 months. We conducted a single-blind randomized controlled trial, comparing the immunogenicity and safety of fractional one-fifth and one-half doses of Bio-Manguinhos 17DD YF vaccine with full dose in children aged 9-23 months old in Uganda. In this paper, we present the interim analysis on safety. METHODS: Children aged 9-23 months presenting for routine well-child services were recruited for inclusion at one of three study sites. We collected data during March 26, 2019-August 31, 2020, on all adverse events following immunization (AEFI) during active surveillance for 28 days post-vaccination using multiple collection tools including a diary card with an objective measurement of fever. An independent team from the Uganda national AEFI Committee investigated and classified serious AEFI (SAE) according to Brighton Collaboration Criteria. RESULTS: Among 1053 enrolled children, 672 (64%) were reported to have a non-serious AEFI (NSAE) and 17 (2%) were reported to have a SAE. The most common AEFI were diarrhoea, fever, and rash, each reported by 355 (34%), 338 (33%), and 188 (18%) participants, respectively. Among 17 participants with SAE, eight were reported to have had seizures and five were hospitalised for seizures or other causes (respiratory symptoms, gastrointestinal illness, malaria). Four SAEs (deaths) occurred >28 days after vaccination. There were no reported cases of pre-specified or vaccine-related SAEs. We observed no significant difference in frequency or severity of adverse events among the study groups. CONCLUSIONS: Using comprehensive active surveillance monitoring, we did not identify any unexpected safety concerns among children aged <2 years receiving YF vaccination, including with the fractional doses. Although we identified a high number of both serious and non-serious AEFI, none were determined to be causally related to YF vaccination. These results provide evidence for the safety of fractional dose YF vaccination among children aged 9-23 months.

Fatal viscerotropic and neurotropic disease after yellow fever vaccine: a rare manifestation leading to diagnosis of severe combined immunodeficiency in an infant.

Yellow fever vaccine (YFV) is a live attenuated vaccine that can cause a mild infection in immunocompetent patients. However, it may not be self-limiting in patients with inborn errors of immunity (IEI) and may be the first and most severe presentation in these patients. A 10-month-old female infant sought emergency care presenting fever for three days and diffuse exanthema. She was a previous healthy child of consanguineous parents. The child had received YFV 28 days before the onset of symptoms. Upon hospital admission, petechial rash on the limbs and hepatosplenomegaly were noted on physical exam. Laboratory tests showed thrombocytopenia, increased serum aminotransferases and elevated gamma-glutamyl transferase (GGT) and alkaline phosphatase levels. During hospitalization she developed hypoactivity, drowsiness, and hypotonia. The possibility of viscerotropic and neurotropic vaccine associated disease was suspected and a possible primary immunodeficiency disease considered. The patient was tested for antibodies against the yellow fever virus (MAC ELISA) on serum and cerebrospinal fluid (CSF) samples, showing positive IgM results. Immunophenotyping showed low levels of lymphocytes and absence of T-cell receptor excision circles (TREC), leading to diagnose of severe combined immunodeficiency disease (SCID). Despite treatment, after 35 days of hospitalization, she evolved to cardiorespiratory arrest and death. Serious adverse events after administration of the YFV are rare and associated with neurological or visceral involvement in most cases. The unfavorable outcome highlights the importance of neonatal screening for SCID and the clinical suspicion of primary immunodeficiencies in infants who have serious adverse events to live virus vaccines.

Vaccine-derived yellow fever in an immunocompromised patient on anti-CD20-antibody therapy and its treatment with sofosbuvir.

Yellow fever (YF) is a potentially lethal viral hemorrhagic fever that can be prevented with the 17D live attenuated YF vaccine. However, this vaccination can cause severe adverse reactions including vaccine-associated YF. Here, we describe the case of a 32-year-old female who was permanently immunosuppressed with an anti-CD20 antibody due to multiple sclerosis. Following YF vaccination, the patient developed a variety of symptoms such as febrile temperatures, muscle and joint pain, headaches, and dysuria. A vaccine-associated YF with viremia was diagnosed. To avoid a potentially severe course of the disease, sofosbuvir was used as antiviral treatment followed by the resolution of symptoms and serological response. As travelers with chronic diseases and immunosuppression will increasingly engage in long distance travel, this case demonstrates the importance of assessing patient history prior to the administration of live vaccines and points towards a possible therapeutic approach in those suffering from vaccine-associated YF.

Live vaccinations in dermatology for immunosuppressed patients: a narrative review.

Given the higher susceptibility to infectious disease in patients receiving immunosuppressive therapies for inflammatory dermatologic conditions, immunization is important in this population. While live vaccines protect against life-threatening diseases, they can be harmful in immunosuppressed patients given the risk of replication of the attenuated pathogen and adverse reactions. The utilization of live vaccines in immunosuppressed patients depends on multiple factors such as the vaccine and therapy regimen. To provide an overview of evidence-based recommendations for the use of live vaccines in patients receiving immunosuppressive therapies for dermatological conditions. A literature search of the PubMed database was performed using keywords live vaccine, live-attenuated vaccine, dermatology, immunosuppressed, and immunocompromised, and specific immunosuppressive therapies: corticosteroids, glucocorticoids, methotrexate, azathioprine, cyclosporine, mycophenolate mofetil, biologics. Relevant articles written in English were included. Using these keywords, 125 articles were reviewed, of which 28 were ultimately selected. Recommendations for live vaccines can be determined on a case-by-case basis. Measles, mumps, rubella, varicella (MMRV) vaccines may be safely administered to patients on low-dose immunosuppressive agents while the yellow fever vaccine is typically contraindicated. It may be safe to administer live MMRV boosters to children on immunosuppressive therapies and the live herpes zoster vaccine to patients on biologics. Given poor adherence to immunization guidelines in immunosuppressed patients, dermatologists have a critical role in educating patients and general practitioners regarding live vaccines. By reviewing a patient's vaccination history and following immunization guidelines prior to initiating immunosuppressive therapies, physicians can mitigate morbidity and mortality from vaccine-preventable diseases.

Safety of the yellow fever vaccine in people living with HIV: a longitudinal study exploring post-vaccination viremia and hematological and liver kinetics.

BACKGROUND: Safety data on the yellow fever vaccine 17DD in People Living with HIV (PLWH) are limited. This study explored the occurrence of post-vaccination 17DD viremia and the kinetics of hematological and liver laboratorial parameters in PLWH and HIV-uninfected participants [HIV(-) controls]. METHODS: We conducted a secondary analysis of a longitudinal interventional trial (NCT03132311) study that enrolled PLWH and HIV(-) controls to receive a single 17DD dose and were followed at 5, 30 and 365 days after vaccination in Rio de Janeiro, Brazil. 17DD viremia (obtained throughreal-time PCR and plaque forming units' assays), hematological (neutrophils, lymphocytes and platelets counts) and liver enzymes (ALT and AST) results were assessed at baseline and Days 5 and 30 post-vaccination. Logistic regression models explored factors associated with the odds of having positive 17DD viremia. Linear regression models explored variables associated with hematological and liver enzymes results at Day 5. RESULTS: A total of 202 PLWH with CD4 ≥ 200 cells/µL and 68 HIV(-) controls were included in the analyses. 17DD viremia was found in 20.0 % of the participants and was twice more frequent in PLWH than in HIV(-) controls (22.8% vs. 11.8 %, p-value < 0.001). Neutrophils, lymphocytes and platelets counts dropped at Day 5 and returned to baseline values at Day 30. 17DD viremia was associated with lower nadir of lymphocytes and platelets at Day 5. ALT levels did not increase post-vaccination and were not associated with 17DD viremia. CONCLUSIONS: 17DD was safe and well-tolerated in PLWH with CD4 ≥ 200 cells/µL. Post-vaccination viremia was more frequent in PLWH than in controls. Transient and self-limited decreases in lymphocytes and neutrophils occurred early after vaccination. 17DD viremia was associated with lower lymphocytes and platelets nadir after vaccination. We did not observe elevations in ALT after 17DD vaccination.

Incidence of anaphylaxis to YF-VAX® yellow fever vaccination: a retrospective evaluation of vaccine adverse event reports 1999-2018.

BACKGROUND: The incidence of anaphylaxis after receipt of yellow fever (YF) vaccine is highly variable based upon previously published reports. Anaphylaxis after receiving the YF vaccine has been reported to range from 0 up to 22 per 1 000 000 doses. Our clinical experience suggested increased incidence, which prompted our investigation. We sought to evaluate the current incidence rate of anaphylaxis after receipt of the 17D-204 strain YF-VAX® brand reported in the US. METHODS: We performed a retrospective review of the Vaccine Adverse Event Reporting System (VAERS) reports of anaphylaxis after receiving the YF-VAX vaccine occurring between 1 October 1999 and 30 September 2018. We utilized the Brighton Collaboration Case Definition and inclusion determination was made by a board-certified allergist. We also obtained the total number of YF-VAX doses distributed across the US during this same time-period and then calculated an updated incidence rate of YF-VAX vaccine-associated anaphylaxis. RESULTS: We identified 132 potential cases of possible or probable anaphylaxis. Of these, 111 met inclusion criteria: level 1 (n = 51), level 2 (n = 59) and level 3 (n = 1). The manufacturer reported a total distribution of 7 624 160 doses of YF-VAX from 1 October 1999 to 30 September 2018. The calculated incidence rate of YF-VAX vaccine-associated anaphylaxis is estimated at 14.6 events per 1 000 000 doses. CONCLUSIONS: We conclude the estimated rate of anaphylaxis per VAERS reports is 14.6 events per 1 000 000 doses after YF-VAX vaccination. This is consistent with some previous reports and substantially higher than rates of anaphylaxis after other vaccines.

Yellow fever vaccine-associated neurologic and viscerotropic disease: a 10-year case series of the French National Reference Center for Arboviruses with clinical and immunological insights.

BACKGROUND: Immunization against the Yellow fever virus (YFV) with the 17D live-attenuated vaccine is the most effective way to prevent the disease. However, unexpected severe adverse events can occur. They consist in a neurological impairment - neurological disease (YEL-AND), a YF-like illness - viscerotropic disease (YEL-AVD) or anaphylaxis. In this article, we describe the epidemiology, clinical and biological features of YEL-AND and YEL-AVD cases reported to the French National Reference Center for Arboviruses (NRCA) in the past 10 years. METHODS: We conducted a national, retrospective study using the database of the NRCA from June 2012 to June 2022. All patients whose biological samples were sent to the NRCA for detection of YFV by serology and/or RT-qPCR for a suspected vaccine-associated adverse event were included. We collected data by reading medical records and conducted complementary neuro-immunological analysis, followed by a search for autoimmunity against type-1-interferon when samples were available at the NRCA. RESULTS: There were 10 cases of YEL-AND and 2 cases of YEL-AVD reported to the NRCA in the past 10 years, which represented an overall incidence of 0.6 for 100 000 doses. A total of 6/12 cases were previously healthy patients (50%, mean age 31 years), and 4/12 cases had cardiovascular co-morbidities (42%, mean age 56 years). The majority of YEL-AND had a favourable outcome at 6 months of follow up. One YEL-AVD patient passed. In secondary analyses, we evidenced a significant blood cerebrospinal fluid (CSF) barrier dysfunction, without intrathecal synthesis of immunoglobulin and without argument for a neuron damage. We further detected a significant rate of anti-type-1alpha interferon antibodies in 3/10 tested patients (2 YEL-AND and 1 YEL-AVD). CONCLUSION: YEL-AND and YEL-AVD are rare events that can underlie defect in the innate immunity of apparently healthy or mild co-morbid subjects. Outcome was generally favourable in the YEL-AND cases of our series, but still life-threatening or even fatal in the YEL-AVD cases.

Frequency of allergic reactions in egg allergic patients after receiving the yellow fever vaccine.

BACKGROUND: Immunization with live attenuated viral yellow fever vaccine (YFV) grants effective immunity in most cases, and is recommended and prioritized for residents and travelers of endemic countries. YFV is seldom administered to egg-allergic patients (EAP) since it is cultivated in embryonated chicken eggs and may contain residual egg proteins, being a problem for egg-allergic residents and travelers of endemic countries. OBJECTIVE: Describe the frequency of allergic reactions after YFV administration in confirmed EAP from an allergy outpatient center in Bogotá, Colombia. METHODS: An observational, retrospective, cross-sectional, and descriptive study was conducted from January 2017 to December 2019. EAP whose allergy was confirmed with a positive Skin Prick Test (SPT) and/or egg protein-specific IgE levels who hadn't received the YFV were included. Every patient had an SPT, severe EAP, and an additional Intradermal Test (IDT) done with the vaccine. If the vaccine SPT and IDT were negative, the YFV was administered as a single dose; if either were positive, the YFV was administered in graded doses. Statistical analysis was done in Stata16MP. RESULTS: Seventy one patients were included, 24 (33.8%) of those had a history of egg anaphylaxis. All patients had negative YFV SPTs, and two of the five YVF IDTs were positive. Two patients, with previous egg-anaphylaxis, presented allergic reactions to the vaccine. CONCLUSIONS: YFV did not trigger allergic reactions in EAP without history of egg-anaphylaxis. With further research, safe single-dose vaccination to this population could be considered; however, patients with previous egg-anaphylaxis should be evaluated by an allergist before vaccination.

Safety and immunogenicity of a purified inactivated Zika virus vaccine candidate in adults primed with a Japanese encephalitis virus or yellow fever virus vaccine in the USA: a phase 1, randomised, double-blind, placebo-controlled clinical trial.

BACKGROUND: Zika virus infection is a threat to at-risk populations, causing major birth defects and serious neurological complications. Development of a safe and efficacious Zika virus vaccine is, therefore, a global health priority. Assessment of heterologous flavivirus vaccination is important given co-circulation of Japanese encephalitis virus and yellow fever virus with Zika virus. We investigated the effect of priming flavivirus naive participants with a licensed flavivirus vaccine on the safety and immunogenicity of a purified inactivated Zika vaccine (ZPIV). METHODS: This phase 1, placebo-controlled, double-blind trial was done at the Walter Reed Army Institute of Research Clinical Trials Center in Silver Spring, MD, USA. Eligible participants were healthy adults aged 18-49 years, with no detectable evidence of previous flavivirus exposure (by infection or vaccination), as measured by a microneutralisation assay. Individuals with serological evidence of HIV, hepatitis B, or hepatitis C infection were excluded, as were pregnant or breastfeeding women. Participants were recruited sequentially into one of three groups (1:1:1) to receive no primer, two doses of intramuscular Japanese encephalitis virus vaccine (IXIARO), or a single dose of subcutaneous yellow fever virus vaccine (YF-VAX). Within each group, participants were randomly assigned (4:1) to receive intramuscular ZPIV or placebo. Priming vaccinations were given 72-96 days before ZPIV. ZPIV was administered either two or three times, at days 0, 28, and 196-234. The primary outcome was occurrence of solicited systemic and local adverse events along with serious adverse events and adverse events of special interest. These data were analysed in all participants receiving at least one dose of ZPIV or placebo. Secondary outcomes included measurement of neutralizing antibody responses following ZPIV vaccination in all volunteers with available post-vaccination data. This trial is registered at ClinicalTrials.gov, NCT02963909. FINDINGS: Between Nov 7, 2016, and Oct 30, 2018, 134 participants were assessed for eligibility. 21 did not meet inclusion criteria, 29 met exclusion criteria, and ten declined to participate. 75 participants were recruited and randomly assigned. 35 (47%) of 75 participants were male and 40 (53%) were female. 25 (33%) of 75 participants identified as Black or African American and 42 (56%) identified as White. These proportions and other baseline characteristics were similar between groups. There were no statistically significant differences in age, gender, race, or BMI between those who did and did not opt into the third dose. All participants received the planned priming IXIARO and YF-VAX vaccinations, but one participant who received YF-VAX dropped out before receipt of the first dose of ZPIV. 50 participants received a third dose of ZPIV or placebo, including 14 flavivirus-naive people, 17 people primed with Japanese encephalitis virus vaccine, and 19 participants primed with yellow fever vaccine. Vaccinations were well tolerated across groups. Pain at the injection site was the only adverse event reported more frequently in participants who received ZPIV than in those who received placebo (39 [65%] of 60 participants, 95% CI 51·6-76·9 who received ZPIV vs three [21·4%] of 14 who received placebo; 4·7-50·8; p=0·006). No patients had an adverse event of special interest or serious adverse event related to study treatment. At day 57, the flavivirus-naive volunteers had an 88% (63·6-98·5, 15 of 17) seroconversion rate (neutralising antibody titre ≥1:10) and geometric mean neutralising antibody titre (GMT) against Zika virus of 100·8 (39·7-255·7). In the Japanese encephalitis vaccine-primed group, the day 57 seroconversion rate was 31·6% (95% CI 12·6-56·6, six of 19) and GMT was 11·8 (6·1-22·8). Participants primed with YF-VAX had a seroconversion rate of 25% (95% CI 8·7-49·1, five of 20) and GMT of 6·6 (5·2-8·4). Humoral immune responses rose substantially following a third dose of ZPIV, with seroconversion rates of 100% (69·2-100; ten of ten), 92·9% (66·1-99·8; 13 of 14), and 60% (32·2-83·7, nine of 15) and GMTs of 511·5 (177·6-1473·6), 174·2 (51·6-587·6), and 79 (19·0-326·8) in the flavivirus naive, Japanese encephalitis vaccine-primed, and yellow fever vaccine-primed groups, respectively. INTERPRETATION: We found ZPIV to be well tolerated in flavivirus naive and primed adults but that immunogenicity varied significantly according to antecedent flavivirus vaccination status. Immune bias towards the flavivirus antigen of initial exposure and the timing of vaccination may have impacted responses. A third ZPIV dose overcame much, but not all, of the discrepancy in immunogenicity. The results of this phase 1 clinical trial have implications for further evaluation of ZPIV's immunisation schedule and use of concomitant vaccinations. FUNDING: Department of Defense, Defense Health Agency; National Institute of Allergy and Infectious Diseases; and Division of Microbiology and Infectious Disease.

Immunogenicity and safety of fractional doses of 17D-213 yellow fever vaccine in HIV-infected people in Kenya (YEFE): a randomised, double-blind, non-inferiority substudy of a phase 4 trial.

BACKGROUND: Evidence indicates that fractional doses of yellow fever vaccine are safe and sufficiently immunogenic for use during yellow fever outbreaks. However, there are no data on the generalisability of this observation to populations living with HIV. Therefore, we aimed to evaluate the immunogenicity of fractional and standard doses of yellow fever vaccine in HIV-positive adults. METHODS: We conducted a randomised, double-blind, non-inferiority substudy in Kilifi, coastal Kenya to compare the immunogenicity and safety of a fractional dose (one-fifth of the standard dose) versus the standard dose of 17D-213 yellow fever vaccine among HIV-positive volunteers. HIV-positive participants aged 18-59 years, with baseline CD4+ T-cell count of at least 200 cells per mL, and who were not pregnant, had no previous history of yellow fever vaccination or infection, and had no contraindication for yellow fever vaccination were recruited from the community. Participants were randomly assigned 1:1 in blocks (variable block sizes) to either a fractional dose or a standard dose of the 17D-213 yellow fever vaccine. Vaccines were administered subcutaneously by an unblinded nurse and pharmacist; all other study personnel were blinded to the vaccine allocation. The primary outcome of the study was the proportion of participants who seroconverted by the plaque reduction neutralisation test (PRNT50) 28 days after vaccination for the fractional dose versus the standard dose in the per-protocol population. Secondary outcomes were assessment of adverse events and immunogenicity during the 1-year follow-up period. Participants were considered to have seroconverted if the post-vaccination antibody titre was at least 4 times greater than the pre-vaccination titre. We set a non-inferiority margin of not less than a 17% decrease in seroconversion in the fractional dose compared with the standard dose. This study is registered with ClinicalTrials.gov, NCT02991495. FINDINGS: Between Jan 29, 2019, and May 17, 2019, 303 participants were screened, and 250 participants were included and vaccinated; 126 participants were assigned to the fractional dose and 124 to the standard dose. 28 days after vaccination, 112 (96%, 95% CI 90-99) of 117 participants in the fractional dose group and 115 (98%, 94-100) of 117 in the standard dose group seroconverted by PRNT50. The difference in seroconversion between the fractional dose and the standard dose was -3% (95% CI -7 to 2). Fractional dosing therefore met the non-inferiority criterion, and non-inferiority was maintained for 1 year. The most common adverse events were headache (n=31 [12%]), fatigue (n=23 [9%]), myalgia (n=23 [9%]), and cough (n=14 [6%]). Reported adverse events were either mild (182 [97%] of 187 adverse events) or moderate (5 [3%]) and were self-limiting. INTERPRETATION: Fractional doses of the 17D-213 yellow fever vaccine were sufficiently immunogenic and safe demonstrating non-inferiority to the standard vaccine dose in HIV-infected individuals with CD4+ T cell counts of at least 200 cells per mL. These results provide confidence that fractional dose recommendations are applicable to populations with high HIV prevalence. FUNDING: Wellcome Trust, Médecins Sans Frontières Foundation, and the UK Department for International Development.

Immunogenicity and safety of fractional doses of 17D-213 yellow fever vaccine in children (YEFE): a randomised, double-blind, non-inferiority substudy of a phase 4 trial.

BACKGROUND: Current supply shortages constrain yellow fever vaccination activities, particularly outbreak response. Although fractional doses of all WHO-prequalified yellow fever vaccines have been shown to be safe and immunogenic in a randomised controlled trial in adults, they have not been evaluated in a randomised controlled trial in young children (9-59 months old). We aimed to assess the immunogenicity and safety of fractional doses compared with standard doses of the WHO-prequalified 17D-213 vaccine in young children. METHODS: This substudy of the YEFE phase 4 study was conducted at the Epicentre Mbarara Research Centre (Mbarara, Uganda). Eligible children were aged 9-59 months without contraindications for vaccination, without history of previous yellow fever vaccination or infection and not requiring yellow fever vaccination for travelling. Participants were randomly assigned, using block randomisation, 1:1 to standard or fractional (one-fifth) dose of yellow fever vaccine. Investigators, participants, and laboratory personnel were blinded to group allocation. Participants were followed for immunogenicity and safety at 10 days, 28 days, and 1 year after vaccination. The primary outcome was non-inferiority in seroconversion (-10 percentage point margin) 28 days after vaccination measured by 50% plaque reduction neutralisation test (PRNT50) in the per-protocol population. Safety and seroconversion at 10 days and 12-16 months after vaccination (given COVID-19 resctrictions) were secondary outcomes. This study is registered with ClinicalTrials.gov, NCT02991495. FINDINGS: Between Feb 20, 2019, and Sept 9, 2019, 433 children were assessed, and 420 were randomly assigned to fractional dose (n=210) and to standard dose (n=210) 17D-213 vaccination. 28 days after vaccination, 202 (97%, 95% CI 95-99) of 207 participants in the fractional dose group and 191 (100%, 98-100) of 191 in the standard dose group seroconverted. The absolute difference in seroconversion between the study groups in the per-protocol population was -2 percentage points (95% CI -5 to 1). 154 (73%) of 210 participants in the fractional dose group and 168 (80%) of 210 in the standard dose group reported at least one adverse event 28 days after vaccination. At 10 days follow-up, seroconversion was lower in the fractional dose group than in the standard dose group. The most common adverse events were upper respiratory tract infections (n=221 [53%]), diarrhoea (n=68 [16%]), rhinorrhoea (n=49 [12%]), and conjunctivitis (n=28 [7%]). No difference was observed in incidence of adverse events and serious adverse events between study groups. CONCLUSIONS: Fractional doses of the 17D-213 vaccine were non-inferior to standard doses in inducing seroconversion 28 days after vaccination in children aged 9-59 months when assessed with PRNT50, but we found fewer children seroconverted at 10 days. The results support consideration of the use of fractional dose of yellow fever vaccines in WHO recommendations for outbreak response in the event of a yellow fever vaccine shortage to include children. FUNDING: Médecins Sans Frontières Foundation.

Yellow fever vaccine hesitancy and its relationship with contextual, individual, or group influences and vaccine-specific issues: a scoping review. / Hesitação da vacina da febre amarela e sua relação com influências contextuais, individuais ou de grupo e questões específicas da vacina: uma revisão de escopo.

Vaccine hesitancy is a phenomenon with the potential to reduce vaccination coverage rates, as observed with the yellow fever vaccine (YFV), leading to epidemics and the reintroduction of controlled immunopreventable diseases. This study, together with the scientific literature, aims to map the relationship among the lack of information, vaccine safety and adverse events, and vaccine hesitancy concerning YFV. A scoping review was conducted in the Virtual Health Library (VHL), National Library of Medicine (PubMed), SCOPUS, Embase, and Web of Science databases, using controlled (DeCS/MeSH) and uncontrolled descriptors. In this work, we selected eleven articles, published in English, Spanish, and Portuguese, with no time limits, which met the inclusion criteria. False information, inadequate knowledge about the immunizer, lack of time to take a vaccination, acceptance of the vaccine, vaccine safety, and fear of adverse events were related to vaccine hesitancy. This study reinforces the importance of access to adequate information, provides guidance on YFV safety and adverse events, and can aid in the development of public health strategies to mitigate hesitancy.

A hesitação vacinal é um fenômeno com potencial para reduzir as taxas de cobertura vacinal, como observado na vacina contra febre amarela (VFA), propiciar epidemias e a reintrodução de doenças imunopreveníveis controladas. O objetivo deste estudo é mapear junto à literatura científica a relação entre a falta de informação, a segurança da vacina e os eventos adversos e a hesitação vacinal da VFA. Foi realizada uma revisão de escopo nas bases Biblioteca Virtual em Saúde (BVS), National Library of Medicine (PubMed), SCOPUS, Embase e Web of Science utilizando descritores controlados (DeCS/MeSH) e não controlados. Foram selecionados 11 artigos publicados nos idiomas inglês, espanhol e português, sem delimitação de tempo e que atenderam aos critérios de inclusão. Estiveram relacionados à hesitação vacinal da VFA informações falsas, conhecimento inadequado sobre o imunizante, falta de tempo para se vacinar, aceitação da vacina, insegurança na vacina e medo dos eventos adversos. Este estudo reforça a importância do acesso a informações adequadas, orientações sobre a segurança e os eventos adversos da VFA e pode auxiliar na elaboração de estratégias de saúde pública para mitigar a hesitação vacinal.

Therapeutic neutralizing monoclonal antibody administration protects against lethal yellow fever virus infection.

Yellow fever virus (YFV) is a reemerging global health threat, driven by several factors, including increased spread of the mosquito vector and rapid urbanization. Although a prophylactic vaccine exists, vaccine hesitancy, supply deficits, and distribution difficulties leave specific populations at risk of severe YFV disease, as evidenced by recent outbreaks in South America. To establish a treatment for patients with severe YFV infection, we tested 37 YFV-specific monoclonal antibodies isolated from vaccinated humans and identified two capable of potently neutralizing multiple pathogenic primary YFV isolates. Using both hamster and nonhuman primate models of lethal YFV infection, we demonstrate that a single administration of either of these two potently neutralizing antibodies during acute infection fully controlled viremia and prevented severe disease and death in treated animals. Given the potential severity of YFV-induced disease, our results show that these antibodies could be effective in saving lives and fill a much-needed void in managing YFV cases during outbreaks.

Enhanced safety surveillance of STAMARIL® yellow fever vaccine provided under the expanded access investigational new drug program in the USA.

BACKGROUND: YF-VAX® (Sanofi, Swiftwater, PA), a live, attenuated vaccine based on the yellow fever (YF) substrain 17D-204, is the only YF vaccine licensed in the USA. Manufacturing disruption of YF-VAX and anticipated depletion of the US supply by mid-2017 led to the importation of another YF vaccine, STAMARIL® (Sanofi, France), into the USA under an expanded access investigational new drug program (EAP) to fulfil the public health need for YF vaccination. As part of this program, Sanofi collected enhanced safety surveillance data following vaccination with STAMARIL. Here, we report the results of the enhanced safety surveillance. METHODS: STAMARIL vaccine was offered to those aged ≥9 months at high risk of YF. Vaccine recipients (or parents/guardians) were instructed to report suspected adverse reactions, any serious adverse events (SAEs) including adverse events of special interest [AESI] occurring after vaccination regardless of suspected relationship, and any inadvertent exposure in pregnancy or breastfeeding within 14 days of vaccination. The AESIs monitored were anaphylaxis, neurotropic disease (YEL-AND) and viscerotropic disease (YEL-AVD). RESULTS: Overall, 627 079 individuals received STAMARIL from May 2017 through June 2021; of these, 1308 (0.2%) reported at least one AE, of which 122 reported at least one SAE. There were seven cases of YEL-AND and three cases of YEL-AVD reported, for reporting rates of 1.1 and 0.5 per 100 000 vaccine recipients, respectively. One vaccine recipient developed an anaphylactic reaction (reporting rate: 0.16 per 100 000). No safety concerns were identified from inadvertent vaccine exposure during pregnancy (41 pregnant women) or potential neonatal exposure via breast milk (four exposed infants). CONCLUSIONS: This study supports the utility of STAMARIL in the EAP as an alternative solution for the YF vaccine shortage in the USA. SAEs were very rare and consistent with the known safety profile of STAMARIL.

Factors associated with yellow fever vaccine failure: A systematic literature review.

INTRODUCTION: Considering that vaccination with yellow fever vaccine (YFV) is the most important method to prevent and control yellow fever (YF), this study synthesized evidence on factors associated with YFV failure. METHODS: A systematic review (SR) was performed in the PubMed, Cochrane CENTRAL, Embase, and LILACS databases up to November 2019. Observational and experimental analytical epidemiological studies that analyzed the failure of YFV were included. This review followed the guidelines of the Preferred Reporting Items for Systematic Reviews and meta-Analyses. RESULTS: A total of 1,466 articles were identified after searching the databases of which 46 were included in the qualitative analysis after applying the elegibility criteria. Our findings indicated that YFV confers protective immunity in different age groups; when produced by different producers; when administered simultaneously with a range of other vaccines; when used as fractional doses and when used with prophylactic and immunosuppressive therapies. It failed to produce a protective response in some pregnant women, children under two years of age, children with Kwashiorkor and when long periods of time have passed after vaccination. For individuals with human immunodeficiency virus (HIV), the results were divergent. CONCLUSIONS: The results of this SR revealed the factors associated with the failure of the YFV, and the results can support recommendations on vaccination policies, support the safety of health professionals who work directly with immunization in the implementation of the vaccination schedule, in addition to guiding future research and enhance the credibility of YFV in the prevention of a serious disease such as YF.

Evaluation of safety and immuno-efficacy of a next generation live-attenuated yellow fever vaccine in cynomolgus macaques.

The increased demand for yellow fever (YF) vaccines over the last decade, along with insufficient availability of specific pathogen-free embryonated eggs required for timely vaccine production, has led to global YF vaccine shortages. A new live-attenuated YF vaccine candidate (generically referred to as vYF) cloned from a YF-VAX® vaccine (YF-17D vaccine) substrain adapted for growth in Vero cells cultured in serum-free media is currently in development. Here, we assessed the safety and immunogenicity of vYF, and its protective activity upon virulent challenge with wild-type yellow fever virus (YFV) Asibi, compared to licensed YF-17D vaccines in the translational cynomolgus macaque model. vYF was well tolerated with no major safety concerns. Vaccine-related safety observations were limited to minimal/minor microscopic findings at the injection sites and in the draining lymph nodes, consistent with expected stimulation of the immune system. vYF induced early differential expression of genes involved in antiviral innate immunity previously described in humans vaccinated with YF-17D vaccines, as well as YFV-specific IgM and IgG antibodies, high and sustained YFV neutralizing antibody titers from Day 14 up to at least Day 258 post-immunization, IgM+ and IgG+ memory B cells from Day 14 up to at least Day 221 post-vaccination, and Th1 interferon (IFN)-γ and interleukin (IL)-2 secreting effector and memory T cells. Additionally, vYF provided effective resistance to virulent challenge with wild-type YFV Asibi including complete protection against YFV-induced mortality, pathology, dysregulation of blood and liver soluble biomarkers, and a significant reduction in viremia and viral load to the limit of detection. These NHP data suggest that vYF would provide protection against YFV infection in practice, at least similar to that achieved with currently marketed YF-17D vaccines.

Yellow fever vaccine safety in immunocompromised individuals: a systematic review and meta-analysis.

BACKGROUND: Yellow fever (YF) is an arbovirus with variable severity, including severe forms with high mortality. The vaccination is the most effective measure to protect against the disease. Non-serious and serious adverse events have been described in immunocompromised individuals, but previous studies have failed to demonstrate this association. This systematic review assessed the risk of adverse events after YF vaccination in immunocompromised individuals compared with its use in non-immunocompromised individuals. METHODS: A search was conducted in the MEDLINE, LILACS, EMBASE, SCOPUS, DARE, Toxiline, Web of Science and grey literature databases for publications until February 2021. Randomized and quasi-randomized clinical trials and observational studies that included immunocompromised participants (individuals with HIV infection, organ transplants, with cancer, who used immunosuppressive drugs for rheumatologic diseases and those on immunosuppressive therapy for other diseases) were selected. The methodological quality of observational or non-randomized studies was assessed by the ROBINS-I tool. Two meta-analyses were performed, proportion and risk factor analyses, to identify the summary measure of relative risk (RR) in the studies that had variables suitable for combination. RESULTS: Twenty-five studies were included, most with risk of bias classified as critical. Thirteen studies had enough data to carry out the proposed meta-analyses. Seven studies without a comparator group had their results aggregated in the proportion meta-analysis, identifying an 8.5% [95% confidence interval (CI) 0.07-21.8] risk of immunocompromised individuals presenting adverse events after vaccination. Six cohort studies were combined, with an RR of 1.00 (95% CI 0.78-1.29). Subgroup analysis was performed according to the aetiology of immunosuppression and was also unable to identify an increased risk of adverse events following vaccination. CONCLUSIONS: It is not possible to affirm that immunocompromised individuals, regardless of aetiology, have a higher risk of adverse events after receiving the YF vaccine.

Autoantibodies against type I IFNs in patients with critical influenza pneumonia.

Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-α2 alone (five patients) or with IFN-ω (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-α2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-ω. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients <70 yr of age (5.7 vs. 1.1%, P = 2.2 × 10-5), but not >70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-α2 and IFN-ω (OR = 11.7, P = 1.3 × 10-5), especially those <70 yr old (OR = 139.9, P = 3.1 × 10-10). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for ∼5% of cases of life-threatening influenza pneumonia in patients <70 yr old.