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.

Immunogenicity and safety of fractional doses of yellow fever vaccines: a randomised, double-blind, non-inferiority trial.

BACKGROUND: Stocks of yellow fever vaccine are insufficient to cover exceptional demands for outbreak response. Fractional dosing has shown efficacy, but evidence is limited to the 17DD substrain vaccine. We assessed the immunogenicity and safety of one-fifth fractional dose compared with standard dose of four WHO-prequalified yellow fever vaccines produced from three substrains. METHODS: We did this randomised, double-blind, non-inferiority trial at research centres in Mbarara, Uganda, and Kilifi, Kenya. Eligible participants were aged 18-59 years, had no contraindications for vaccination, were not pregnant or lactating, had no history of yellow fever vaccination or infection, and did not require yellow fever vaccination for travel. Eligible participants were recruited from communities and randomly assigned to one of eight groups, corresponding to the four vaccines at standard or fractional dose. The vaccine was administered subcutaneously by nurses who were not masked to treatment, but participants and other study personnel were masked to vaccine allocation. The primary outcome was proportion of participants with seroconversion 28 days after vaccination. Seroconversion was defined as post-vaccination neutralising antibody titres at least 4 times pre-vaccination measurement measured by 50% plaque reduction neutralisation test (PRNT50). We defined non-inferiority as less than 10% decrease in seroconversion in fractional compared with standard dose groups 28 days after vaccination. The primary outcome was measured in the per-protocol population, and safety analyses included all vaccinated participants. This trial is registered with ClinicalTrials.gov, NCT02991495. FINDINGS: Between Nov 6, 2017, and Feb 21, 2018, 1029 participants were assessed for inclusion. 69 people were ineligible, and 960 participants were enrolled and randomly assigned to vaccine manufacturer and dose (120 to Bio-Manguinhos-Fiocruz standard dose, 120 to Bio-Manguinhos-Fiocruz fractional dose, 120 to Chumakov Institute of Poliomyelitis and Viral Encephalitides standard dose, 120 to Chumakov Institute of Poliomyelitis and Viral Encephalitides fractional dose, 120 to Institut Pasteur Dakar standard dose, 120 to Institut Pasteur Dakar fractional dose, 120 to Sanofi Pasteur standard dose, and 120 to Sanofi Pasteur fractional dose). 49 participants had detectable PRNT50 at baseline and 11 had missing PRNT50 results at baseline or 28 days. 900 were included in the per-protocol analysis. 959 participants were included in the safety analysis. The absolute difference in seroconversion between fractional and standard doses by vaccine was 1·71% (95% CI -2·60 to 5·28) for Bio-Manguinhos-Fiocruz, -0·90% (-4·24 to 3·13) for Chumakov Institute of Poliomyelitis and Viral Encephalitides, 1·82% (-2·75 to 5·39) for Institut Pasteur Dakar, and 0·0% (-3·32 to 3·29) for Sanofi Pasteur. Fractional doses from all four vaccines met the non-inferiority criterion. The most common treatment-related adverse events were headache (22·2%), fatigue (13·7%), myalgia (13·3%) and self-reported fever (9·0%). There were no study-vaccine related serious adverse events. INTERPRETATION: Fractional doses of all WHO-prequalified yellow fever vaccines were non-inferior to the standard dose in inducing seroconversion 28 days after vaccination, with no major safety concerns. These results support the use of fractional dosage in the general adult population for outbreak response in situations of vaccine shortage. FUNDING: The study was funded by Médecins Sans Frontières Foundation, Wellcome Trust (grant no. 092654), and the UK Department for International Development. Vaccines were donated in kind.

Safety and immunogenicity of 17DD attenuated yellow fever vaccine in howler monkeys (Alouatta spp.).

BACKGROUND: Alouatta spp. are highly susceptible to yellow fever (YF) infection and develop an often fatal disease. The threat posed by an outbreak started in 2016 leads us to investigate vaccination as a potential tool in preventing YF in non-human primates (NHP). METHODS: Susceptible howler monkeys were immunized with three different concentrations of the human Brazilian commercial YF17DD vaccine. Post-vaccination viremia/RNAemia, immunogenicity, and safety were characterized. RESULTS: The vaccine did not produce YF clinical manifestations in any of the NHPs. After immunization, all animals seroconverted demonstrating the ability of the YF vaccine to induce humoral response in Alouatta species. CONCLUSIONS: The present work has demonstrated the safe and immunogenic profile of the existing YF 17DD vaccine in howler monkeys. This knowledge may support further studies with other susceptible monkey species and provide a possible solution for controlling epizootics and preventing the devastation of endangered species.

Viscerotropic disease and acute uveitis following yellow fever vaccination: a case report.

BACKGROUND: Yellow fever vaccine exists for over 80 years and is considered to be relatively safe. However, in rare cases it can produce serious neurotropic and viscerotropic complications. We report a case of a patient who presented both viscerotropic and neurological manifestations after yellow fever vaccination. CASE PRESENTATION: We describe the case of a 37 years old man who developed after the yellow fever vaccination a yellow fever vaccine-associated viscerotropic disease followed by acute uveitis. Prolonged detection of yellow fever RNA in blood and urine was consistent with yellow fever vaccine-associated adverse event. The final outcome was good, although with persistent fatigue over a few months. CONCLUSIONS: Even if the yellow fever vaccine is relatively safe, physicians should be aware of its possible serious adverse effects.

Fulminant MS Reactivation Following Combined Fingolimod Cessation and Yellow Fever Vaccination.

A major concern caused by the discontinuation of disease modifying treatment for multiple sclerosis (MS) is a rebound of disease activity. Hypotheses about the underlying mechanism of fingolimod (FTY) induced exaggerated inflammatory responses are diverse. So far, vaccinations as a trigger for rebound activity following FTY suspension have not been described. However, several reports have highlighted the occurrence of neurological and autoimmune side effects after single or combined multi-vaccination procedures. Here, we describe the case of a highly active female MS patient demonstrating recurrent, severe MS relapses accompanied by extensive MRI activity, subsequent to yellow fever vaccination two months following FTY withdrawal. Blood and cerebrospinal fluid immunophenotyping indicated a B cell/plasma cell autoreactivity. Following a therapy with natalizumab the clinical, laboratory, MRI, and disease course improved significantly. This case hints towards a combined immunological mechanism characterized by molecular mimicry, bystander activation, and lymphocyte re-egress, resulting in extensive neurological impairment and shows that natalizumab represents a therapeutic option to counteract B cell mediated autoreactivity. Especially, the diagnostic and therapeutic management of this complex scenario might be instructive for clinical practice.

Immunogenicity and Safety of Yellow Fever Vaccine in Allogeneic Hematopoietic Stem Cell Transplant Recipients After Withdrawal of Immunosuppressive Therapy.

As a live attenuated vaccine, yellow fever vaccine (YFV) is not routinely performed after allogeneic hematopoietic stem cell transplant (HSCT) despite it being the only efficient preventive therapy. We retrospectively identified 21 HSCT recipients immunized with YFV at a median of 39 months after HSCT and a median of 33 months after withdrawal of immunosuppression without any side effects. Eighteen evaluable patients had protective immunity after YFV. We also observed that a third of the recipients vaccinated with YFV before HSCT had persistent protective immunity after HSCT.

Development of a Real-Time Reverse Transcription-PCR Assay for Global Differentiation of Yellow Fever Virus Vaccine-Related Adverse Events from Natural Infections.

Yellow fever (YF) is a reemerging public health threat, with frequent outbreaks prompting large vaccination campaigns in regions of endemicity in Africa and South America. Specific detection of vaccine-related adverse events is resource-intensive, time-consuming, and difficult to achieve during an outbreak. To address this, we have developed a highly transferable rapid yellow fever virus (YFV) vaccine-specific real-time reverse transcription-PCR (RT-PCR) assay that distinguishes vaccine from wild-type lineages. The assay utilizes a specific hydrolysis probe that includes locked nucleic acids to enhance specific discrimination of the YFV17D vaccine strain genome. Promisingly, sensitivity and specificity analyses reveal this assay to be highly specific to vaccine strain(s) when tested on clinical samples and YFV cell culture isolates of global origin. Taken together, our data suggest the utility of this assay for use in laboratories of varied capacity for the identification and differentiation of vaccine-related adverse events from wild-type infections of both African and South American origin.

Meningomyeloradiculitis following yellow fever 17D vaccination: a case report.

The yellow fever 17D vaccine contains live-attenuated virus. Initial efficacy and safety reports were favorable. Recently, however, neurologic and viscerotropic adverse events (AE) were described. We managed a 61-year-old man who experienced meningomyeloradiculitis 18 days after receiving the yellow fever 17D vaccine. The manifestations were atypical. The cerebrospinal fluid contained high titers of anti-yellow fever immunoglobulins M and G and of anti-flavivirus immunoglobulins G. After methylprednisolone (1 g/day for 3 days), intravenous human immunoglobulins (140 g over 5 days), and two plasma exchanges, the symptoms improved only slightly. Neurological adverse events after yellow fever vaccination are rare or underestimated. To our knowledge, this is the first reported case of meningomyeloradiculitis after yellow fever vaccination. A remarkable feature is the intrathecal production of yellow fever antibodies, which probably played a pathogenic role and may have been related to a recent episode of influenza.

What Controls the Acute Viral Infection Following Yellow Fever Vaccination?

Does target cell depletion, innate immunity, or adaptive immunity play the dominant role in controlling primary acute viral infections? Why do some individuals have higher peak virus titers than others? Answering these questions is a basic problem in immunology and can be particularly difficult in humans due to limited data, heterogeneity in responses in different individuals, and limited ability for experimental manipulation. We address these questions for infections following vaccination with the live attenuated yellow fever virus (YFV-17D) by analyzing viral load data from 80 volunteers. Using a mixed effects modeling approach, we find that target cell depletion models do not fit the data as well as innate or adaptive immunity models. Examination of the fits of the innate and adaptive immunity models to the data allows us to select a minimal model that gives improved fits by widely used model selection criteria (AICc and BIC) and explains why it is hard to distinguish between the innate and adaptive immunity models. We then ask why some individuals have over 1000-fold higher virus titers than others and find that most of the variation arises from differences in the initial/maximum growth rate of the virus in different individuals.

[Anti-NMDAR encephalitis as a serious adverse event probably related to yellow fever vaccination].

We present a case of a 17-year-old female with anti-NMDAR encephalitis probably associated with vaccination against yellow fever. Her symptoms occurred 27 days after vaccination against yellow fever. Anti-NMDAR encephalitis manifested as acute psychosis, memory loss and catatonia following fever with complex partial epileptic seizures. Interictal electroencephalogram showed slow-wave delta background activity with "delta brushes". The diagnosis was confirmed by NMDAR antibody positivity in serum and cerebrospinal fluid. Since ovarian teratoma, as the most common cause of anti-NMDAR encephalitis, did not develop within five years from its onset, the association with vaccination against yellow fever seems to be highly probable.

[Guideline for fecal bacteriotherapy to treat recurrent Clostridium difficile colitis].

We present a case of a 17-year-old female with anti-NMDAR encephalitis probably associated with vaccination against yellow fever. Her symptoms occurred 27 days after vaccination against yellow fever. Anti-NMDAR encephalitis manifested as acute psychosis, memory loss and catatonia following fever with complex partial epileptic seizures. Interictal electroencephalogram showed slow-wave delta background activity with "delta brushes". The diagnosis was confirmed by NMDAR antibody positivity in serum and cerebrospinal fluid. Since ovarian teratoma, as the most common cause of anti-NMDAR encephalitis, did not develop within five years from its onset, the association with vaccination against yellow fever seems to be highly probable.

The Yellow Fever Vaccine Misadventure of 1942.

In 1942, a hepatitis B outbreak occurred in the US Army after vaccination with contaminated lots of 17D yellow fever vaccine; long-term sequelae were surprisingly limited, and retrospective studies of carrier rates, cirrhosis, and hepatocellular carcinoma were found to be minimal. Later studies identified the contaminant as hepatitis B virus (HBV) in the human serum component of the vaccine. Other than 2 follow-up studies of long-term sequelae and reports within US Military archives, the event has never been fully elucidated in its proper historical context in the medical literature available through MEDLINE (PubMed). The outbreak resulted in nearly 50 000 clinical cases, including 29 000 cases of overt jaundice. More than 300 000 troops may have been infected with HBV. The decision to immunize troops received criticism, but the decision may have been reasonable, given the exigencies of an impending war and the possibility that yellow fever could spread to future theaters of war. The epidemic was the largest and most well-documented vaccine-related epidemic in history. Today, independent of war, globalization has actually increased the likelihood of yellow fever importations to vulnerable areas of the world.

Yellow fever vaccine-associated neurotropic disease (YEL-AND) - A case report.

Yellow fever (YF) is a mosquito-borne viral hemorrhagic fever, which is a serious and potentially fatal disease with no specific antiviral treatment that can be effectively prevented by an attenuated vaccine (YEL). Despite the long history of safe and efficacious YF vaccination, sporadic case reports of serious adverse events (SAEs) have been reported, including yellow fever vaccine-associated neurotropic disease (YEL-AND). YEL-AND usually appears within one month of YF vaccination, manifesting as meningoencephalitis, Guillain-Barré syndrome (GBS) or acute disseminated encephalomyelitis (ADEM). We report a case of YEL-AND with meningitis presentation in a 39-year-old Caucasian man without evidence of significant risk factors, which was confirmed by the presence of the YF virus and specific immunoglobulin G (IgG) antibodies in the cerebrospinal fluid (CSF). In conclusion, we should stress the importance of balancing the risk of SAEs associated with the vaccine and the benefits of YF vaccination for each patient individually.

Notes from the field: fatal yellow fever vaccine-associated viscerotropic disease--Oregon, September 2014.

In September 2014, a previously healthy Oregon woman in her 60s went to a hospital emergency department with malaise, dyspnea, vomiting, and diarrhea of 3-5 days' duration. She reported no recent travel, ill contacts, or dietary changes. Six days earlier, she had received a single dose of yellow fever vaccine and typhoid vaccine before planned travel to South America.

Yellow Fever Vaccine Booster Doses: Recommendations of the Advisory Committee on Immunization Practices, 2015.

On February 26, 2015, the Advisory Committee on Immunization Practices (ACIP) voted that a single primary dose of yellow fever vaccine provides long-lasting protection and is adequate for most travelers. ACIP also approved recommendations for at-risk laboratory personnel and certain travelers to receive additional doses of yellow fever vaccine (Box). The ACIP Japanese Encephalitis and Yellow Fever Vaccines Workgroup evaluated published and unpublished data on yellow fever vaccine immunogenicity and safety. The evidence for benefits and risks associated with yellow fever vaccine booster doses was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. This report summarizes the evidence considered by ACIP and provides the updated recommendations for yellow fever vaccine booster doses.

A public health risk assessment for yellow fever vaccination: a model exemplified by an outbreak in the state of São Paulo, Brazil.

We propose a method to analyse the 2009 outbreak in the region of Botucatu in the state of São Paulo (SP), Brazil, when 28 yellow fever (YF) cases were confirmed, including 11 deaths. At the time of the outbreak, the Secretary of Health of the State of São Paulo vaccinated one million people, causing the death of five individuals, an unprecedented number of YF vaccine-induced fatalities. We apply a mathematical model described previously to optimise the proportion of people who should be vaccinated to minimise the total number of deaths. The model was used to calculate the optimum proportion that should be vaccinated in the remaining, vaccine-free regions of SP, considering the risk of vaccine-induced fatalities and the risk of YF outbreaks in these regions.

A randomised double-blind clinical trial of two yellow fever vaccines prepared with substrains 17DD and 17D-213/77 in children nine-23 months old.

This randomised, double-blind, multicentre study with children nine-23 months old evaluated the immunogenicity of yellow fever (YF) vaccines prepared with substrains 17DD and 17D-213/77. YF antibodies were titered before and 30 or more days after vaccination. Seropositivity and seroconversion were analysed according to the maternal serological status and the collaborating centre. A total of 1,966 children were randomised in the municipalities of the states of Mato Grosso do Sul, Minas Gerais and São Paulo and blood samples were collected from 1,714 mothers. Seropositivity was observed in 78.6% of mothers and 8.9% of children before vaccination. After vaccination, seropositivity rates of 81.9% and 83.2%, seroconversion rates of 84.8% and 85.8% and rates of a four-fold increase over the pre-vaccination titre of 77.6% and 81.8% were observed in the 17D-213/77 and 17DD subgroups, respectively. There was no association with maternal immunity. Among children aged 12 months or older, the seroconversion rates of 69% were associated with concomitant vaccination against measles, mumps and rubella. The data were not conclusive regarding the interference of maternal immunity in the immune response to the YF vaccine, but they suggest interference from other vaccines. The failures in seroconversion after vaccination support the recommendation of a booster dose in children within 10 years of the first dose.

Transcutaneous yellow fever vaccination of subjects with or without atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease with a global prevalence ranging from 3% to 20%. Patients with AD have an increased risk for complications after viral infection (eg, herpes simplex virus), and vaccination of patients with AD with live vaccinia virus is contraindicated because of a heightened risk of eczema vaccinatum, a rare but potentially lethal complication associated with smallpox vaccination. OBJECTIVE: We sought to develop a better understanding of immunity to cutaneous viral infection in patients with AD. METHODS: In a double-blind randomized study we investigated the safety and immunogenicity of live attenuated yellow fever virus (YFV) vaccination of nonatopic subjects and patients with AD after standard subcutaneous inoculation or transcutaneous vaccination administered with a bifurcated needle. Viremia, neutralizing antibody, and antiviral T-cell responses were analyzed for up to 30 days after vaccination. RESULTS: YFV vaccination administered through either route was well tolerated. Subcutaneous vaccination resulted in higher seroconversion rates than transcutaneous vaccination but elicited similar antiviral antibody levels and T-cell responses in both the nonatopic and AD groups. After transcutaneous vaccination, both groups mounted similar neutralizing antibody responses, but patients with AD demonstrated lower antiviral T-cell responses by 30 days after vaccination. Among transcutaneously vaccinated subjects, a significant inverse correlation between baseline IgE levels and the magnitude of antiviral antibody and CD4(+) T-cell responses was observed. CONCLUSIONS: YFV vaccination of patients with AD through the transcutaneous route revealed that high baseline IgE levels provide a potential biomarker for predicting reduced virus-specific immune memory after transcutaneous infection with a live virus.