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1.
Vaccine ; 39(13): 1846-1856, 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33685778

RESUMEN

Yellow fever (YF) remains a threat to human health in tropical regions of Africa and South America. Live-attenuated YF-17D vaccines have proven to be safe and effective in protecting travellers and populations in endemic regions against YF, despite very rare severe reactions following vaccination - YF vaccine-associated viscerotropic disease (YEL-AVD) and neurological disease (YEL-AND). We describe the generation and selection of a live-attenuated YF-17D vaccine candidate and present its preclinical profile. Initially, 24 YF-17D vaccine candidate sub-strains from the Stamaril® and YF-VAX® lineage were created through transfection of viral genomic RNA into Vero cells cultured in serum-free media to produce seed lots. The clone with the 'optimal' preclinical profile, i.e. the lowest neurovirulence, neurotropism and viscerotropism, and immunogenicity at least comparable with Stamaril and YF-VAX in relevant animal models, was selected as the vaccine candidate and taken forward for assessment at various production stages. The 'optimal' vaccine candidate was obtained from the YF-VAX lineage (hence named vYF-247) and had five nucleotide differences relative to its parent, with only two changes that resulted in amino acid changes at position 480 of the envelope protein (E) (valine to leucine), and position 65 of the non-structural protein 2A (NS2A) (methionine to valine). vYF-247 was less neurovirulent in mice than Stamaril and YF-VAX irrespective of production stage. Its attenuation profile in terms of neurotropism and viscerotropism was similar to YF-VAX in A129 mice, a 'worst case' animal model lacking type-I IFN receptors required to initiate viral clearance. Thus, vYF-247 would not be expected to have higher rates of YEL-AVD or YEL-AND than Stamaril and YF-VAX. In hamsters, vYF-247 was immunogenic and protected against high viremia and death induced by a lethal challenge with the hamster-adapted Jimenez P10 YF virus strain. Our data suggests that vYF-247 would provide robust protection against YF disease in humans, similar to currently marketed YF vaccines.

2.
J Exp Med ; 218(4)2021 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-33544838

RESUMEN

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Autoanticuerpos/inmunología , Enfermedades Autoinmunes , Enfermedades Genéticas Congénitas , Interferón-alfa , Receptor de Interferón alfa y beta , Vacuna contra la Fiebre Amarilla , Virus de la Fiebre Amarilla , Adolescente , Adulto , Anciano , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , /inmunología , Femenino , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/inmunología , Células HEK293 , Humanos , Interferón-alfa/genética , Interferón-alfa/inmunología , Masculino , Persona de Mediana Edad , Receptor de Interferón alfa y beta/deficiencia , Receptor de Interferón alfa y beta/inmunología , /inmunología , Vacunas Atenuadas/genética , Vacunas Atenuadas/inmunología , Vacuna contra la Fiebre Amarilla/efectos adversos , Vacuna contra la Fiebre Amarilla/genética , Vacuna contra la Fiebre Amarilla/inmunología , Virus de la Fiebre Amarilla/genética , Virus de la Fiebre Amarilla/inmunología
3.
Lancet ; 397(10269): 76-77, 2021 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-33422247
4.
Lancet ; 397(10269): 119-127, 2021 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-33422245

RESUMEN

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.

5.
Nature ; 2020 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-33260195

RESUMEN

The explosively expanding COVID-19 pandemic urges the development of safe, efficacious and fast-acting vaccines. Several vaccine platforms are leveraged for a rapid emergency response1. We describe the discovery of a live virus-vectored SARS-CoV-2 vaccine candidate using the yellow fever 17D (YF17D) vaccine as vector to express a non-cleavable prefusion form of the SARS-CoV-2 Spike antigen. We assess vaccine safety, immunogenicity and efficacy in several animal models. Vaccine candidate YF-S0 has an outstanding safety profile and induces high levels of SARS-CoV-2 neutralizing antibodies in hamsters, mice and cynomolgus macaques and concomitantly a protective immunity against YFV. Humoral immunity is complemented by a favourable Th1 cell-mediated immune response as profiled in mice. In a stringent hamster model2 as well as in non-human primates, YF-S0 prevents infection with SARS-CoV-2. Moreover, in hamsters, a single dose confers protection from lung disease in most vaccinated animals within 10 days. Taken together, the quality of immune responses triggered and the rapid kinetics by which protective immunity can be mounted already after a single dose warrant further development this potent SARS-CoV-2 vaccine candidate.

6.
Rev Soc Bras Med Trop ; 53: e20200787, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33331614

RESUMEN

INTRODUCTION: Since 2016, Brazil has been in the midst of its largest sylvatic yellow fever epidemic ever, found predominantly outside the Amazon region. Cases originating from Brazil have been reported in France, the Netherlands, Romania, Switzerland, Argentina, and Chile. The epidemic began in the Central-West region of Brazil in 2014, spreading into the Southern region, with significant non-human primate transmission continuing towards Paraguay and Argentina. METHODS: This report is an integrative review of Pan American Health Organization cooperation during a sylvatic yellow fever epidemic. RESULTS: The Pan American Health Organization has played a central role in handling the yellow fever emergency, collaborating with the Ministry of Health and various research groups in supporting interventions of different response areas. The Pan American Health Organization's technical cooperation included: training and workshops to exchange experiences, carrying out technical cooperation in patient management and epidemiological, entomological, laboratory, and epizootic surveillance, organizing the assistance network, and acquiring strategic inputs. The Pan American Health Organization's technical cooperation supported the Ministry of Health's decision to adopt a single-dose vaccine and use fractional doses to support the vaccination needs of more than 39,000,000 people. The coronavirus disease 2019 pandemic contributed to the failure of reaching the yellow fever vaccination goals and made it difficult to integrate the yellow fever vaccine into recommended areas. CONCLUSIONS: Given the ongoing coronavirus disease 2019 pandemic, it is necessary to strengthen measures for the surveillance, prevention, and control of yellow fever with multilateral cooperation between countries.


Asunto(s)
Fiebre Amarilla , Argentina , Brasil , Brotes de Enfermedades , Francia , Humanos , Organización Panamericana de la Salud , Pandemias , Paraguay , Fiebre Amarilla/epidemiología , Fiebre Amarilla/prevención & control , Virus de la Fiebre Amarilla
7.
J Med Primatol ; 2020 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-33219623

RESUMEN

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.

8.
Front Immunol ; 11: 577751, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33133096

RESUMEN

Introduction: Although effective live attenuated yellow fever (YF) vaccines have been available for over 9 decades sporadic outbreaks continue to occur in endemic regions. These may be linked to several factors including epidemiological factors such as vector and intermediate host distribution or vaccine coverage and efficacy. The World Health Organization's research priorities include gathering systematic evidence around the potential need for booster vaccination with YF vaccine whether this follows full or fractional doses in children. Knowledge on the longevity of response to YF vaccine and the implications of this response needs to be consolidated to guide future vaccination policy. Methods: We measured anti-YF IgG by microneutralization assay in a group of 481 African infants who had received YF vaccine as part of routine EPI programmes, to explore serological protection from YF 5-6 years post YF vaccination, as well as the effect of co variates. Findings: Notably, 22.2% of the cohort had undetectable antibody concentrations, with another 7.5% revealing concentrations below the threshold of seropositivity of 0.5 IU/mL. Sex, season, country and time since vaccination did not affect the longevity of antibody concentration or having antibody concentrations above a defined threshold. Conclusion: Roughly 30% of children in this cohort did not demonstrate anti-yellow fever antibody concentrations above the defined threshold of protection, with 20% having no demonstrable antibody. Knowledge on the longevity of response to YF vaccine and the implications needs to be consolidated to guide future vaccination policy.

9.
Int J Appl Comput Math ; 6(4): 105, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32835032

RESUMEN

In this study, a deterministic model for the transmission dynamics of yellow fever (YF) in a human-mosquito setting in the presence of control measures is constructed and rigorously analyzed. In addition to horizontal transmissions, vertical transmission within mosquito population is incorporated. Analysis of the mosquito-only component of the model shows that the reduced model has a mosquito-extinction equilibrium, which is globally-asymptotically stable whenever the basic offspring number ( N 0 ) is less than unity. The vaccinated and type reproduction numbers of the full-model are computed. Condition for global-asymptotic stability of the disease-free equilibrium of the model when N 0 > 1 is presented. It is shown that, fractional dosing of YF vaccine does not meet YF vaccination requirements. Optimal control theory is applied to the model to characterize the controls parameters. Using Pontryagin's maximum principle and modified forward-backward sweep technique, the necessary conditions for existence of solutions to the optimal control problem is determined. Numerical simulations of the models to assess the effect of fractional vaccine dosing on the disease dynamics and global sensitivity analysis are presented.

10.
Preprint | bioRxiv | ID: ppbiorxiv-193045

RESUMEN

The explosively expanding COVID-19 pandemic urges the development of safe, efficacious and fast-acting vaccines to quench the unrestrained spread of SARS-CoV-2. Several promising vaccine platforms, developed in recent years, are leveraged for a rapid emergency response to COVID-191. We employed the live-attenuated yellow fever 17D (YF17D) vaccine as a vector to express the prefusion form of the SARS-CoV-2 Spike antigen. In mice, the vaccine candidate, tentatively named YF-S0, induces high levels of SARS-CoV-2 neutralizing antibodies and a favorable Th1 cell-mediated immune response. In a stringent hamster SARS-CoV-2 challenge model2, vaccine candidate YF-S0 prevents infection with SARS-CoV-2. Moreover, a single dose confers protection from lung disease in most vaccinated animals even within 10 days. These results warrant further development of YF-S0 as a potent SARS-CoV-2 vaccine candidate.

11.
Hum Vaccin Immunother ; 16(9): 2196-2203, 2020 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-32574095

RESUMEN

Plasmid-launched live-attenuated vaccines (PLLAV), also called infectious DNA (iDNA) vaccines, combine the assets of genetic immunization with the potency of replication-competent live viral vaccines. However, due to their origin as bacterial plasmid DNA, efficient delivery of PLLAV may be hampered by innate signaling pathways such as the cGAS-STING-mediated sensing of cytosolic DNA, resulting in an unfavorable proinflammatory and antiviral response locally at the site of immunization. Employing several complementary cell-based systems and using the yellow fever vaccine (YF17D) and the respective PLLAV-YF17D, we screened a panel of small molecules known to interfere with antiviral signaling for their proviral activity and identified two potent inhibitors of the TANK-binding kinase 1 (TBK1), BX795 and CYT387, to enhance YF17D replication and hence efficacy of PLLAV-YF17D transfection. In tissue culture, BX795 could fully revert the block that plasmid transfection poses on YF17D infection in a type I interferon dependent manner, as confirmed by (i) a marked change in gene expression signatures, (ii) a rescue of full YF17D replication, and (iii) a massively increased virus yield. Inhibitors of TBK1 may hence be considered an adjuvant to potentiate novel PLLAV vaccines, which might boost PLLAV delivery toward their use in vivo.

12.
Viruses ; 12(5)2020 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-32397218

RESUMEN

Live-attenuated vaccines (LAVs) have achieved remarkable successes in controlling virus spread, as well as for other applications such as cancer immunotherapy. However, with rapid increases in international travel, globalization, geographic spread of viral vectors, and widespread use of vaccines, there is an increasing need to consider how pre-exposure to viruses which share similar antigenic regions can impact vaccine efficacy. Pre-existing antibodies, derived from either from maternal-fetal transmission, or by previous infection or vaccination, have been demonstrated to interfere with vaccine immunogenicity of measles, adenovirus, and influenza LAVs. Immune interference of LAVs can be caused by the formation of virus-antibody complexes that neutralize virus infection in antigen-presenting cells, or by the cross-linking of the B-cell receptor with the inhibitory receptor, FcgRIIB. On the other hand, pre-existing antibodies can augment flaviviral LAV efficacy such as that of dengue and yellow fever virus, especially when pre-existing antibodies are present at sub-neutralizing levels. The increased vaccine immunogenicity can be facilitated by antibody-dependent enhancement of virus infection, enhancing virus uptake in antigen-presenting cells, and robust induction of innate immune responses that promote vaccine immunogenicity. This review examines the literature on this topic and examines the circumstances where pre-existing antibodies can inhibit or enhance LAV efficacy. A better knowledge of the underlying mechanisms involved could allow us to better manage immunization in seropositive individuals and even identify possibilities that could allow us to exploit pre-existing antibodies to boost vaccine-induced responses for improved vaccine efficacy.

13.
J Virol ; 94(10)2020 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-32132233

RESUMEN

Members of the flavivirus genus share a high level of sequence similarity and often circulate in the same geographical regions. However, whether T cells induced by one viral species cross-react with other related flaviviruses has not been globally addressed. In this study, we tested pools of epitopes derived from dengue (DENV), Zika (ZIKV), Japanese encephalitis (JEV), West Nile (WNV), and yellow fever (YFV) viruses by intracellular cytokine staining (ICS) using peripheral blood mononuclear cells (PBMCs) of individuals naturally exposed to DENV or immunized with DENV (TV005) or YF17D vaccine. CD8 T cell responses recognized epitopes from multiple flaviviruses; however, the magnitude of cross-reactive responses was consistently severalfold lower than those to the autologous epitope pools and was associated with lower expression of activation markers such as CD40L, CD69, and CD137. Next, we characterized the antigen sensitivity of short-term T cell lines (TCL) representing 29 different individual epitope/donor combinations. TCL derived from DENV monovalent vaccinees induced CD8 and CD4 T cells that cross-reacted within the DENV serocomplex but were consistently associated with >100-fold-lower antigen sensitivity for most other flaviviruses, with no cross-recognition of YFV-derived peptides. CD8 and CD4 TCL from YF17D vaccinees were associated with very limited cross-reactivity with any other flaviviruses and in five out of eight cases >1,000-fold-lower antigen sensitivity. Overall, our data suggest limited cross-reactivity for both CD4 and CD8 T cell responses between flaviviruses and have implications for understanding immunity elicited by natural infection and strategies to develop live attenuated vaccines against flaviviral species.IMPORTANCE The envelope (E) protein is the dominant target of neutralizing antibodies for dengue virus (DENV) and yellow fever virus (YFV). Accordingly, several DENV vaccine constructs use the E protein in a live attenuated vaccine format, utilizing a backbone derived from a heterologous flavivirus (such as YF) as a delivery vector. This backbone comprises the nonstructural (NS) and capsid (C) antigens, which are dominant targets of T cell responses. Here, we demonstrate that cross-reactivity at the level of T cell responses among different flaviviruses is very limited, despite high levels of sequence homology. Thus, the use of heterologous flavivirus species as a live attenuated vaccine vector is not likely to generate optimal T cell responses and might thus impair vaccine performance.


Asunto(s)
Reacciones Cruzadas/inmunología , Infecciones por Flavivirus/inmunología , Flavivirus/inmunología , Vacunación , Vacunas Atenuadas/inmunología , Vacunas Virales/inmunología , Adolescente , Adulto , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos/inmunología , Dengue/inmunología , Dengue/prevención & control , Vacunas contra el Dengue/inmunología , Virus del Dengue/inmunología , Encefalitis Japonesa/inmunología , Encefalitis Japonesa/prevención & control , Epítopos de Linfocito T/genética , Femenino , Infecciones por Flavivirus/prevención & control , Humanos , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Homología de Secuencia , Fiebre del Nilo Occidental/inmunología , Fiebre del Nilo Occidental/prevención & control , Fiebre Amarilla/inmunología , Fiebre Amarilla/prevención & control , Vacuna contra la Fiebre Amarilla , Virus de la Fiebre Amarilla/inmunología , Adulto Joven , Virus Zika/inmunología , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/prevención & control
14.
Proc Natl Acad Sci U S A ; 117(12): 6675-6685, 2020 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-32152119

RESUMEN

A comprehensive understanding of the development and evolution of human B cell responses induced by pathogen exposure will facilitate the design of next-generation vaccines. Here, we utilized a high-throughput single B cell cloning technology to longitudinally track the human B cell response to the yellow fever virus 17D (YFV-17D) vaccine. The early memory B cell (MBC) response was mediated by both classical immunoglobulin M (IgM) (IgM+CD27+) and switched immunoglobulin (swIg+) MBC populations; however, classical IgM MBCs waned rapidly, whereas swIg+ and atypical IgM+ and IgD+ MBCs were stable over time. Affinity maturation continued for 6 to 9 mo following vaccination, providing evidence for the persistence of germinal center activity long after the period of active viral replication in peripheral blood. Finally, a substantial fraction of the neutralizing antibody response was mediated by public clones that recognize a fusion loop-proximal antigenic site within domain II of the viral envelope glycoprotein. Overall, our findings provide a framework for understanding the dynamics and complexity of human B cell responses elicited by infection and vaccination.


Asunto(s)
Anticuerpos Antivirales/inmunología , Antígenos Virales/inmunología , Linfocitos B/inmunología , Memoria Inmunológica/inmunología , Vacuna contra la Fiebre Amarilla/inmunología , Fiebre Amarilla/prevención & control , Virus de la Fiebre Amarilla/inmunología , Adulto , Humanos , Vacunación , Vacunas Atenuadas/inmunología , Proteínas del Envoltorio Viral/inmunología , Replicación Viral , Fiebre Amarilla/inmunología , Fiebre Amarilla/virología , Vacuna contra la Fiebre Amarilla/administración & dosificación
15.
Elife ; 92020 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-32081129

RESUMEN

The diverse repertoire of T-cell receptors (TCR) plays a key role in the adaptive immune response to infections. Using TCR alpha and beta repertoire sequencing for T-cell subsets, as well as single-cell RNAseq and TCRseq, we track the concentrations and phenotypes of individual T-cell clones in response to primary and secondary yellow fever immunization - the model for acute infection in humans - showing their large diversity. We confirm the secondary response is an order of magnitude weaker, albeit ∼10 days faster than the primary one. Estimating the fraction of the T-cell response directed against the single immunodominant epitope, we identify the sequence features of TCRs that define the high precursor frequency of the two major TCR motifs specific for this particular epitope. We also show the consistency of clonal expansion dynamics between bulk alpha and beta repertoires, using a new methodology to reconstruct alpha-beta pairings from clonal trajectories.

16.
Vaccines (Basel) ; 8(1)2020 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-31973073

RESUMEN

Live-attenuated vaccines (LAV) represent one of the most important medical innovations in human history. In the past three centuries, LAV have saved hundreds of millions of lives, and will continue to do so for many decades to come. Interestingly, the most successful LAVs, such as the smallpox vaccine, the measles vaccine, and the yellow fever vaccine, have been isolated and/or developed in a purely empirical manner without any understanding of the immunological mechanisms they trigger. Today, the mechanisms governing potent LAV immunogenicity and long-term induced protective immunity continue to be elusive, and therefore hamper the rational design of innovative vaccine strategies. A serious roadblock to understanding LAV-induced immunity has been the lack of suitable and cost-effective animal models that can accurately mimic human immune responses. In the last two decades, human-immune system mice (HIS mice), i.e., mice engrafted with components of the human immune system, have been instrumental in investigating the life-cycle and immune responses to multiple human-tropic pathogens. However, their use in LAV research has remained limited. Here, we discuss the strong potential of LAVs as tools to enhance our understanding of human immunity and review the past, current and future contributions of HIS mice to this endeavor.

17.
Artículo en Inglés | MEDLINE | ID: mdl-31938550

RESUMEN

Yellow fever (YF) outbreaks continue, have expanded into new areas and threaten large populations in South America and Africa. Predicting where epidemics might occur must take into account local mosquito populations and specific YF virus strain, as well as ecoclimatic conditions, sociopolitical and demographic factors including population size, density, and mobility, and vaccine coverage. Populations of Aedes aegypti and Aedes albopictus from different regions vary in susceptibility to and capacity to transmit YF virus. YF virus cannot be eliminated today because the virus circulates in animal reservoirs, but human disease could be eliminated with wide use of the vaccine. WHO EYE (Eliminate Yellow Fever Epidemics) is a welcome plan to control YF, with strategies to be carried out from 2017 to 2026: to expand use of YF vaccine, to prevent international spread, and to contain outbreaks rapidly. YF vaccination is the mainstay in controlling YF outbreaks, but global supply is insufficient. Therefore, dose-sparing strategies have been proposed including fractional dosing and intradermal administration. Fractional dosing has been effectively used in outbreak control but currently does not satisfy International Health Regulations; special documentation is needed for international travel. Vector control is another facet in preventing YF outbreaks, and novel methods are being considered and proposed.

18.
J Theor Biol ; 486: 110085, 2020 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-31758966

RESUMEN

The control strategies of emergency infectious diseases are constrained by limited medical resources. The fractional dose vaccination strategy as one of feasible strategies was proposed in response to global shortages of vaccine stockpiles. Although a variety of epidemic models have been developed under the circumstances of limited resources in treatment, few models particularly investigated vaccination strategies in resource-limited settings. In this paper, we develop a two-group SIR model with incorporation of proportionate mixing patterns and n-fold fractional dose vaccination related parameters to evaluate the efficiency of fractional dose vaccination on disease control at the population level. The existence and uniqueness of the final size of the two-group SIR epidemic model, the formulation of the basic reproduction number and the relationship between them are established. Moreover, numerical simulations are performed based on this two-group vector-free model to investigate the effectiveness of n-fold fractional dose vaccination by using the emergency outbreaks of yellow fever in Angola in 2016. By employing linear and nonlinear dose-response relationships, we compare the resulting fluctuations of four characteristics of the epidemics, which are the outbreak size, the peak time of the outbreak, the basic reproduction number and the infection attack rate (IAR). For both types of dose-response relationships, dose-fractionation takes positive effects in lowering the outbreak size, delay the peak time of the outbreak, reducing the basic reproduction number and the IAR of yellow fever only when the vaccine efficacy is high enough. Moreover, five-fold fractional dose vaccination strategy may not be the optimal vaccination strategy as proposed by the World Health Organization if the dose-response relationship is nonlinear.

19.
Vaccine ; 38(6): 1291-1301, 2020 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-31859201

RESUMEN

BACKGROUND: Recent upsurges in yellow fever outbreaks are increasing the demand for yellow fever vaccine, while enormously straining global vaccine supply. Fractional dose yellow fever vaccination is being considered as a dose-sparing strategy to address current vaccine shortages. This systematic review and meta-analysis aimed to assess the effects of fractional dose yellow fever vaccination, in comparison with those of standard dose vaccination. METHODS: We registered this review on the International Prospective Register of Systematic Reviews (PROSPERO, registration number: CRD42018084214), developed the protocol in line with the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols (PRISMA-P) and synthesised the evidence in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). We stratified meta-analyses by vaccine dose. RESULTS: We retrieved 2524 records from the literature search, eleven of them potentially eligible. From these studies, we included eight eligible trials, with a total of 2371 participants. Seroconversion rates at four to five weeks following vaccination were similar between participants who received standard doses and participants who received fractional doses containing one-third (547 participants: risk ratio [RR] 1.02, 95% confidence interval [CI] 1.00-1.04), one-fifth (155 participants: RR 1.00, 95% CI 0.98-1.03), one-tenth (890 participants: RR 0.99, 95% CI 0.96-1.01), and one-fiftieth (661 participants: RR 0.97, 95% CI 0.92-1.02) of the standard dose. However, the rates of seroconversion were substantially lower among participants who received fractional doses containing one-hundredth and lower fractions of the standard dose. Immunogenicity similarly persisted 8-10 years following both fractional and standard dose vaccination. Minor adverse events following vaccination did not differ across doses, and no serious adverse events were reported in any study arm. CONCLUSIONS: These findings support the use of fractional dosing as a strategy for mitigating vaccine shortages. The strategy should be specifically considered for individuals who are young, immuno-competent and well nourished.

20.
Hum Vaccin Immunother ; 16(4): 900-903, 2020 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-31634051

RESUMEN

Yellow fever has been recently described in nonurban areas of Brazil despite 80 years of commercial vaccine use. Although the disease does not spread fear in the general population as it did in the past, yellow fever virus continues to cause many cases of severe disease. Persistence of the virus in the host is a new mechanism to be considered in the pathology of the disease. Immunization with a fractional dose of vaccine during emergency situations needs to be evaluated for antibody duration, and new and improved vaccines should be considered.

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