RESUMO
The non-human primate (NHP) model (specifically rhesus and cynomolgus macaques) has facilitated our understanding of the pathogenic mechanisms of yellow fever (YF) disease and allowed the evaluation of the safety and efficacy of YF-17D vaccines. However, the accuracy of this model in mimicking vaccine-induced immunity in humans remains to be fully determined. We used a systems biology approach to compare hematological, biochemical, transcriptomic, and innate and antibody-mediated immune responses in cynomolgus macaques and human participants following YF-17D vaccination. Immune response progression in cynomolgus macaques followed a similar course as in adult humans but with a slightly earlier onset. Yellow fever virus neutralizing antibody responses occurred earlier in cynomolgus macaques [by Day 7[(D7)], but titers > 10 were reached in both species by D14 post-vaccination and were not significantly different by D28 [plaque reduction neutralization assay (PRNT)50 titers 3.6 Log vs 3.5 Log in cynomolgus macaques and human participants, respectively; P = 0.821]. Changes in neutrophils, NK cells, monocytes, and T- and B-cell frequencies were higher in cynomolgus macaques and persisted for 4 weeks versus less than 2 weeks in humans. Low levels of systemic inflammatory cytokines (IL-1RA, IL-8, MIP-1α, IP-10, MCP-1, or VEGF) were detected in either or both species but with no or only slight changes versus baseline. Similar changes in gene expression profiles were elicited in both species. These included enriched and up-regulated type I IFN-associated viral sensing, antiviral innate response, and dendritic cell activation pathways D3-D7 post-vaccination in both species. Hematological and blood biochemical parameters remained relatively unchanged versus baseline in both species. Low-level YF-17D viremia (RNAemia) was transiently detected in some cynomolgus macaques [28% (5/18)] but generally absent in humans [except one participant (5%; 1/20)].IMPORTANCECynomolgus macaques were confirmed as a valid surrogate model for replicating YF-17D vaccine-induced responses in humans and suggest a key role for type I IFN.
Assuntos
Macaca fascicularis , Modelos Animais , Vacina contra Febre Amarela , Animais , Feminino , Humanos , Masculino , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Imunidade Inata , Biologia de Sistemas/métodos , Vacinação , Febre Amarela/prevenção & controle , Febre Amarela/imunologia , Febre Amarela/virologia , Vacina contra Febre Amarela/imunologia , Vírus da Febre Amarela/imunologiaRESUMO
Recent data obtained with the live-attenuated tetravalent dengue CYD-TDV vaccine showed higher protective efficacy against dengue virus type 4 (DENV-4) than against DENV-2. In contrast, results from previous studies in nonhuman primates predicted comparable high levels of protection against each serotype. Maximum viral loads achieved in macaques by subcutaneous inoculation of DENV are generally much lower than those observed in naturally dengue virus-infected humans. This may contribute to an overestimation of vaccine efficacy. Using more-stringent DENV infection conditions consisting of the intravenous inoculation of 107 50% cell culture infectious doses (CCID50) in CYD-TDV-vaccinated macaques, complete protection (i.e., undetectable viral RNA) was achieved in all 6 monkeys challenged with DENV-4 and in 6/18 of those challenged with DENV-2, including transiently positive animals. All other infected macaques (12/18) developed sustained DENV-2 RNAemia (defined as detection of viral RNA in serum samples) although 1 to 3 log10 units below the levels achieved in control animals. Similar results were obtained with macaques immunized with either CYD-TDV or monovalent (MV) CYD-2. This suggests that partial protection against DENV-2 was mediated mainly by CYD-2 and not by the other CYDs. Postchallenge induction of strong anamnestic responses, suggesting efficient vaccine priming, likely contributed to the reduction of DENV-2 RNAemia. Finally, an inverse correlation between DENV RNA titers postchallenge and vaccine-induced homotypic neutralizing antibody titers prechallenge was found, emphasizing the key role of these antibodies in controlling DENV infection. Collectively, these data show better agreement with reported data on CYD-TDV clinical vaccine efficacy against DENV-2 and DENV-4. Despite inherent limitations of the nonhuman primate model, these results reinforce its value in assessing the efficacy of dengue vaccines.IMPORTANCE The nonhuman primate (NHP) model is the most widely recognized tool for assessing the protective activity of dengue vaccine candidates, based on the prevention of postinfection DENV viremia. However, its use has been questioned after the recent CYD vaccine phase III trials, in which moderate protective efficacy against DENV-2 was reported, despite full protection against DENV-2 viremia previously being demonstrated in CYD-vaccinated monkeys. Using a reverse translational approach, we show here that the NHP model can be improved to achieve DENV-2 protection levels that show better agreement with clinical efficacy. With this new model, we demonstrate that the injection of the CYD-2 component of the vaccine, in either a monovalent or a tetravalent formulation, is able to reduce DENV-2 viremia in all immunized animals, and we provide clear statistical evidence that DENV-2-neutralizing antibodies are able to reduce viremia in a dose-dependent manner.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra Dengue/imunologia , Vírus da Dengue/imunologia , Dengue/imunologia , Carga Viral/veterinária , Animais , Dengue/prevenção & controle , Dengue/virologia , Vírus da Dengue/genética , Modelos Animais de Doenças , Macaca fascicularis , Masculino , RNA Viral/sangue , Resultado do Tratamento , Vacinação , Carga Viral/imunologia , Viremia/prevenção & controleRESUMO
BACKGROUND: Recent outbreaks between 2015-17 and production delays have led to a yellow fever vaccine shortage. Therefore, there is an urgent need for new yellow fever vaccines with improved production scalability. A next-generation live-attenuated yellow fever vaccine candidate (vYF), produced in a Vero cell line has shown similar immunogenicity to licensed yellow fever vaccines in preclinical studies. In this study, we aimed to report the safety and immunogenicity of vYF in human clinical trial participants. METHODS: In this first in-human, phase 1 randomised, observer-blind, active-controlled, dose-ranging clinical trial conducted at a single centre in the USA (Walter Reed Army Institute of Research, Silver Spring, MD, USA), 72 healthy adults (aged 18-60 years), without a known history of flavivirus infection or vaccination were randomly assigned (1:1:1:1) using interactive response technology to receive one dose of either vYF at 4, 5 or 6 Log CCID50 or the licensed YF-VAX (18 individuals per group). The primary outcomes were safety, neutralising antibody (NAb) titres through D180 post-vaccination in the per-protocol analysis set (comprised of yellow fever-naive participants who received their intended vaccine and provided a valid post-vaccination blood sample), and occurrence, and level of yellow fever viraemia in each vaccine group through D14 post-vaccination. FINDINGS: All vYF doses had a safety and tolerability profile similar to YF-VAX. The most frequently reported solicited injection site reactions (vYF groups vs YF-VAX group) were pain (22% [12 of 54 participants, 95% CI 12-36] vs 28% [five of 18 participants, 10-54]), and erythema (13% [seven of 54 participants, 5-25] vs 39% [seven of 18 participants, 17-64]), with headache (32% [17 of 54 participants, 20-46] vs 44% [eight of 18 participants, 22-69]) and malaise (26% [14 of 54 participants, 15-40] vs 33% [six of 18 participants, 13-59]) as the most frequently reported solicited systemic reactions. One grade 3 solicited reaction (erythema) reported in the YF-VAX group resolved spontaneously. No serious unsolicited adverse events or deaths were reported. Viraemia was transiently detected in 50 participants between D4 and D10 in all groups and was observed in more participants or for a longer time in the vYF 6 Log CCID50 and YF-VAX groups. All yellow fever-naive vaccine recipients across the study groups seroconverted yielding four-fold increase from baseline in yellow fever NAb titres measured by yellow fever microneutralisation assay by D28 and were seroprotected with yellow fever NAb titres of at least 10 [1/dil]). Overall, 100% (18 of 18 participants, 95% CI 82-100), 89% (16 participants, 65-99), 100% (18 participants, 82-100), and 94% (17 participants, 73-100) of participants in the vYF 4 Log, vYF 5 Log, vYF 6 Log CCID50 groups, and YF-VAX group, respectively, remained seroprotected through D180. INTERPRETATION: vYF has a similar safety and immunogenicity profile to YF-VAX. In general, the vYF 5 Log CCID50 dose appeared to show optimal viraemia, safety, and immunogenicity, and was chosen for subsequent development. FUNDING: Sanofi.
RESUMO
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.
Assuntos
Vacina contra Febre Amarela , Febre Amarela , Humanos , Animais , Chlorocebus aethiops , Vacina contra Febre Amarela/efeitos adversos , Células Vero , Febre Amarela/prevenção & controle , Vírus da Febre Amarela , Anticorpos Antivirais , Antígenos Virais , Macaca , Vacinas AtenuadasRESUMO
Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection, leading to a variety of symptoms in the unborn child that range from asymptomatic to death in utero. Our objective was to better understand the mechanisms of placental infection by HCMV clinical strains, particularly during the first trimester of pregnancy. We thus characterized and compared the replication kinetics of various HCMV clinical strains and laboratory strains by measuring viral loads in an ex vivo model of first trimester villi and decidua, and used NGS and PCA analysis to analyze the genes involved in cell tropism and virulence factors. We observed that first trimester villi and decidua are similarly permissive to laboratory and symptomatic strains, and that asymptomatic strains poorly replicate in decidua tissue. PCA analysis allowed us to segregate our clinical strains based on their clinical characteristics, suggesting a link between gene mutations and symptoms. All these results bring forth elements that can help better understand the mechanisms that induce the appearance of symptoms or in the congenitally infected newborn.
RESUMO
One of the most effective vaccines against an arbovirus is the YFV-17D live-attenuated vaccine developed in 1937 against Yellow Fever (YF). This vaccine replicates poorly in mosquitoes and consequently, is not transmitted by vectors. Vaccine shortages, mainly due to constrained productions based on pathogen-free embryonated eggs, led Sanofi to move towards alternative methods based on a state-of-the-art process using continuous cell line cultures in bioreactor. vYF-247 is a next-generation live-attenuated vaccine candidate based on 17D adapted to grow in serum-free Vero cells. For the development of a new vaccine, WHO recommends to document infectivity and replication in mosquitoes. Here we infected Aedes aegypti and Aedes albopictus mosquitoes with vYF-247 vaccine compared first to the YF-17D-204 reference Sanofi vaccines (Stamaril and YF-VAX) and a clinical human isolate S-79, provided in a blood meal at a titer of 6.5 Log ffu/mL and secondly, to the clinical isolate only at an increased titer of 7.5 Log ffu/mL. At different days post-infection, virus replication, dissemination and transmission were evaluated by quantifying viral particles in mosquito abdomen, head and thorax or saliva, respectively. Although comparison of vYF-247 to reference vaccines could not be completed to yield significant results, we showed that vYF-247 was not transmitted by both Aedes species, either laboratory strains or field-collected populations, compared to clinical strain S-79 at the highest inoculation dose. Combined with the undetectable to low level viremia detected in vaccinees, transmission of the vYF-247 vaccine by mosquitoes is highly unlikely.
Assuntos
Aedes , Vacina contra Febre Amarela , Febre Amarela , Chlorocebus aethiops , Animais , Humanos , Vacinas Atenuadas , Células Vero , Mosquitos Vetores , Febre Amarela/prevenção & controle , Antígenos Virais , Vírus da Febre AmarelaRESUMO
Mass vaccination with the live attenuated vaccine YF-17D is the current way to prevent infection with Yellow fever virus (YFV). However, 0.000012-0.00002% of vaccinated patients develop post-vaccination neurological syndrome (YEL-AND). Understanding the factors responsible for neuroinvasion, neurotropism, and neurovirulence of the vaccine is critical for improving its biosafety. The YF-FNV vaccine strain, known to be associated with a higher frequency of YEL-AND (0.3-0.4%) than YF-17D, is an excellent model to study vaccine neuroinvasiveness. We determined that neuroinvasiveness of YF-FNV occured both via infection and passage through human brain endothelial cells. Plaque purification and next generation sequencing (NGS) identified several neuroinvasive variants. Their neuroinvasiveness was not higher than that of YF-FNV. However, rebuilding the YF-FNV population diversity from a set of isolated YF-FNV-N variants restored the original neuroinvasive phenotype of YF-FNV. Therefore, we conclude that viral population diversity is a critical factor for YFV vaccine neuroinvasiveness.
RESUMO
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.
Assuntos
Vacina contra Febre Amarela , Febre Amarela , África , Animais , Chlorocebus aethiops , Cricetinae , Camundongos , Modelos Animais , América do Sul , Vacinas Atenuadas , Células Vero , Febre Amarela/prevenção & controle , Vacina contra Febre Amarela/efeitos adversos , Vírus da Febre Amarela/genéticaRESUMO
Absence of 'live' residual poliovirus in Inactivated Poliovirus Vaccine (IPV) is routinely checked using Primary Monkey Kidney Cells (PMKC). However, the increasing demand for IPV and the ethical, technical and safety issues associated with the use of non-human primates in research and quality control, has made the replacement of primary cells with an established cell line a priority, in line with the principles of the 3Rs (Replacement, Reduction and Refinement in animal testing). As an alternative to PMKC, we evaluated the L20B cell line; a mouse cell-line genetically engineered to express human poliovirus receptor, CD155. L20B is already used for the detection and diagnosis of poliovirus in clinical samples. We demonstrate the stability of L20B cells in terms of CD155 gene and receptor expression, and permissivity to polioviruses for at least 16 sequential passages. In addition, the L20B cell line was found to be at least as sensitive as PMKC in detecting the presence of 'live' poliovirus in IPV samples. Equivalence or superiority of L20B cells versus PMKCs was demonstrated for assessing the presence of residual 'live' poliovirus in formaldehyde-inactivated preparations for the three poliovirus serotypes. These results demonstrate that the L20B cell line is a suitable alternative to PMKC in IPV inactivation testing.
Assuntos
Poliomielite/prevenção & controle , Vacina Antipólio de Vírus Inativado/imunologia , Poliovirus/imunologia , Animais , Linhagem Celular , Feminino , Dosagem de Genes , Haplorrinos , Humanos , Masculino , Poliomielite/genética , Poliomielite/imunologia , Poliomielite/virologia , Poliovirus/genética , Receptores Virais/genética , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: The first licensed dengue vaccine is a recombinant, live, attenuated, tetravalent dengue virus vaccine (CYD-TDV; Sanofi Pasteur). This study assessed the biodistribution, shedding, and toxicity of CYD-TDV in a non-human primate model as part of the nonclinical safety assessment program for the vaccine. METHODS: Cynomolgus monkeys were given one subcutaneous injection of either one human dose (5log10 CCID50/serotype) of CYD-TDV or saline control. Study endpoints included clinical observations, body temperature, body weight, food consumption, clinical pathology, immunogenicity, and post-mortem examinations including histopathology. Viral load, distribution, persistence, and shedding in tissues and body fluids were evaluated by quantitative reverse transcriptase polymerase chain reaction. RESULTS: The subcutaneous administration of CYD-TDV was well tolerated. There were no toxicological findings other than expected minor local reactions at the injection site. A transient low level of CYD-TDV viral RNA was detected in blood and the viral genome was identified primarily at the injection site and in the draining lymph nodes following immunization. CONCLUSIONS: These results, together with other data from repeat-dose toxicity and neurovirulence studies, confirm the absence of toxicological concern with CYD-TDV and corroborate clinical study observations.
Assuntos
Vacinas contra Dengue/efeitos adversos , Vacinas contra Dengue/imunologia , Dengue/prevenção & controle , Macaca fascicularis/imunologia , Distribuição Tecidual/imunologia , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Animais , Anticorpos Antivirais/imunologia , Dengue/imunologia , Vírus da Dengue/imunologia , Feminino , Genoma Viral/imunologia , Macaca fascicularis/virologia , Masculino , Vacinação/efeitos adversos , Carga Viral/imunologiaRESUMO
Recently, several virus studies have shown that protein glycosylation play a fundamental role in the virus-host cell interaction. Glycosylation characterization of the envelope proteins in both insect and mammalian cell-derived dengue virus (DENV) has established that two potential glycosylation residues, the asparagine 67 and 153 can potentially be glycosylated. Moreover, it appears that the glycosylation of these two residues can influence dramatically the virus production and the infection spreading in either mosquito or mammalian cells. The Sanofi Pasteur tetravalent dengue vaccine (CYD) consists of four chimeric viruses produced in mammalian vero cells. As DENV, the CYDs are able to infect human monocyte-derived dendritic cells in vitro via C-type lectins cell-surface molecules. Despite the importance of this interaction, the specific glycosylation pattern of the DENV has not been clearly documented so far. In this paper, we investigated the structure of the N-linked glycans in the four CYD serotypes. Using MALDI-TOF analysis, the N-linked glycans of CYDs were found to be a mix of high-mannose, hybrid and complex glycans. Site-specific N-glycosylation analysis of CYDs using nanoLC-ESI-MS/MS demonstrates that both asparagine residues 67 and 153 are glycosylated. Predominant glycoforms at asparagine 67 are high mannose-type structures while mainly complex- and hybrid-type structures are detected at asparagine 153. In vitro studies have shown that the immunological consequences of infection by the CYD dengue viruses 1-4 versus the wild type parents are comparable in human monocyte-derived dendritic cells. Our E-protein glycan characterizations of CYD are consistent with those observations from the wild type parents and thus support in vitro studies. In addition, these data provide new insights for the role of glycans in the dengue virus-host cell interactions.
Assuntos
Vacinas contra Dengue/química , Vírus da Dengue , Proteínas do Envelope Viral/química , Animais , Asparagina/química , Chlorocebus aethiops , Glicosilação , Humanos , Lectinas Tipo C/metabolismo , Manose/metabolismo , Polissacarídeos/química , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Células Vero , Proteínas do Envelope Viral/isolamento & purificaçãoRESUMO
The objective of the study was to evaluate if the antibodies elicited after immunization with a tetravalent dengue vaccine, based on chimeric yellow fever 17D/dengue viruses, can neutralize a large range of dengue viruses (DENV). A panel of 82 DENVs was developed from viruses collected primarily during the last decade in 30 countries and included the four serotypes and the majority of existing genotypes. Viruses were isolated and minimally amplified before evaluation against a tetravalent polyclonal serum generated during vaccine preclinical evaluation in monkey, a model in which protection efficacy of this vaccine has been previously demonstrated (Guirakhoo et al., 2004). Neutralization was observed across all the DENV serotypes, genotypes, geographical origins and isolation years. These data indicate that antibodies elicited after immunization with this dengue vaccine candidate should widely protect against infection with contemporary DENV lineages circulating in endemic countries.
Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Vacinas contra Dengue/imunologia , Vírus da Dengue/imunologia , Portadores de Fármacos , Vetores Genéticos , Vírus da Febre Amarela/genética , Animais , Linhagem Celular , Chlorocebus aethiops , Vacinas contra Dengue/administração & dosagem , Vacinas contra Dengue/genética , Vírus da Dengue/genética , Genótipo , Macaca fascicularis , Testes de Neutralização , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologiaRESUMO
Chimeric yellow fever 17D/DENV-1-4 viruses (CYD-1-4) have been developed as a tetravalent dengue vaccine candidate which is currently being evaluated in efficacy trials in Asia and America. While YF 17D and DENV are mosquito-borne flaviviruses, it has been shown that CYD-1-4 do not replicate after oral infection in mosquitoes and are not transmitted to new hosts. To further document the risk of environmental dissemination of these viruses, we evaluated the replication of CYD-1-4 in ticks, the vector of tick-borne encephalitis virus (TBEV), another member of the flavivirus family. Females of two hard tick species, Ixodes ricinus and Rhipicephalus appendiculatus, were inoculated intracoelomically with CYD-1-4 viruses and parent viruses (DENV-1-4 and YF 17D). Virus persistence and replication was assessed 2, 16, and 44 days post-inoculation by plaque titration and qRT-PCR. CYD-1-4 viruses were detected in I. ricinus ticks at early time points post-inoculation, but with infectious titers at least 100-fold lower than those observed in TBEV-infected ticks. Unlike TBEV, complete viral clearance occurred by day 44 in most ticks except for CYD-2, which had a tendency to decline. In addition, while about 70% of TBEV-infected I. ricinus nymphs acquired infection by co-feeding with infected tick females on non-viremic hosts, no co-feeding transmission of CYD-2 virus was detected. Based on these results, we conclude that the risk of dissemination of the candidate vaccine viruses by tick bite is highly unlikely.
Assuntos
Vírus da Dengue/imunologia , Dengue/transmissão , Flavivirus/imunologia , Ixodes/virologia , Rhipicephalus/virologia , Febre Amarela/transmissão , Animais , Quimera , Culicidae/virologia , Dengue/prevenção & controle , Dengue/virologia , Vírus da Dengue/fisiologia , Feminino , Flavivirus/fisiologia , Humanos , Vacinas Virais , Replicação Viral , Febre Amarela/prevenção & controle , Febre Amarela/virologiaRESUMO
Interferences between different antigens in the same vaccine formulation have been reported for some vaccines (e.g., polio vaccines, live attenuated dengue vaccine candidates). We examined interferences between the four serotypes of ChimeriVax dengue vaccines (CYDs) in a monkey model when present within a tetravalent formulation in equal concentrations (TV-5555). Immunoassays of vaccinated non-human primates showed that serotype 4 (DEN-4), and to a lesser extent, DEN-1 were dominant in terms of neutralizing antibody levels. Parameters that affected the interferences were identified, including 1) the simultaneous administration of two complementary bivalent vaccines at separate anatomical sites drained by different lymph nodes; 2) the sequential administration of two complementary bivalent vaccines; 3) the establishment of heterologous flavivirus pre-immunity before subsequent tetravalent immunization; 4) the adaptation of formulations by decreasing the dose of the immunodominant serotype; and 5) the administration of a 1-year booster. The applicability of these data to human responses is discussed.