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1.
Hum Vaccin Immunother ; : 1-8, 2020 Jun 23.
Article in English | MEDLINE | ID: mdl-32574095

ABSTRACT

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.

2.
Viruses ; 12(5)2020 May 08.
Article in English | MEDLINE | ID: mdl-32397218

ABSTRACT

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.

3.
J Virol ; 94(10)2020 May 04.
Article in English | MEDLINE | ID: mdl-32132233

ABSTRACT

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.

4.
Proc Natl Acad Sci U S A ; 117(12): 6675-6685, 2020 03 24.
Article in English | MEDLINE | ID: mdl-32152119

ABSTRACT

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.


Subject(s)
Antibodies, Viral/immunology , Antigens, Viral/immunology , B-Lymphocytes/immunology , Immunologic Memory/immunology , Yellow Fever Vaccine/immunology , Yellow Fever/prevention & control , Yellow fever virus/immunology , Adult , Humans , Vaccination , Vaccines, Attenuated/immunology , Viral Envelope Proteins/immunology , Virus Replication , Yellow Fever/immunology , Yellow Fever/virology , Yellow Fever Vaccine/administration & dosage
5.
Elife ; 92020 Feb 21.
Article in English | MEDLINE | ID: mdl-32081129

ABSTRACT

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.

6.
Hum Vaccin Immunother ; 16(4): 900-903, 2020 Apr 02.
Article in English | MEDLINE | ID: mdl-31634051

ABSTRACT

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.

7.
J Theor Biol ; 486: 110085, 2020 Feb 07.
Article in English | MEDLINE | ID: mdl-31758966

ABSTRACT

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.

8.
Vaccine ; 38(6): 1291-1301, 2020 02 05.
Article in English | MEDLINE | ID: mdl-31859201

ABSTRACT

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.

9.
São Paulo; SES/SP; 2020. 13 p.
Non-conventional in Portuguese | LILACS, Sec. Est. Saúde SP, SESSP-CTDPROD, Sec. Est. Saúde SP, SESSP-ACVSES | ID: biblio-1052919

Subject(s)
Yellow Fever , Vaccines , Aedes
10.
Emerg Microbes Infect ; 8(1): 1734-1746, 2019.
Article in English | MEDLINE | ID: mdl-31797751

ABSTRACT

By infecting mice with the yellow fever virus vaccine strain 17D (YFV-17D; Stamaril®), the dose dependence and evolutionary consequences of neurotropic yellow fever infection was assessed. Highly susceptible AG129 mice were used to allow for a maximal/unlimited expansion of the viral populations. Infected mice uniformly developed neurotropic disease; the virus was isolated from their brains, plaque purified and sequenced. Viral RNA populations were overall rather homogenous [Shannon entropies 0-0.15]. The remaining, yet limited intra-host population diversity (0-11 nucleotide exchanges per genome) appeared to be a consequence of pre-existing clonal heterogeneities (quasispecies) of Stamaril®. In parallel, mice were infected with a molecular clone of YFV-17D which was in vivo launched from a plasmid. Such plasmid-launched YFV-17D had a further reduced and almost clonal evolution. The limited intra-host evolution during unrestricted expansion in a highly susceptible host is relevant for vaccine and drug development against flaviviruses in general. Firstly, a propensity for limited evolution even upon infection with a (very) low inoculum suggests that fractional dosing as implemented in current YF-outbreak control may pose only a limited risk of reversion to pathogenic vaccine-derived virus variants. Secondly, it also largely lowers the chance of antigenic drift and development of resistance to antivirals.


Subject(s)
Evolution, Molecular , Genetic Variation , Yellow Fever/virology , Yellow fever virus/genetics , Animals , Antibodies, Viral/blood , Brain/pathology , Brain/virology , Disease Models, Animal , Mice , Plasmids/genetics , Yellow Fever Vaccine
11.
mBio ; 10(5)2019 10 22.
Article in English | MEDLINE | ID: mdl-31641088

ABSTRACT

The molecular basis of attenuation for live-attenuated vaccines is poorly understood. The yellow fever (YF) 17D vaccine virus was derived from the wild-type, parental strain Asibi virus by serial passage in chicken tissue and has proven to be a very safe and efficacious vaccine. We have previously shown that wild-type Asibi is a typical RNA virus with high genetic diversity, while the 17D vaccine virus has very little genetic diversity. To investigate this further, we treated Asibi and 17D viruses with ribavirin, a GTP analog with strong antiviral activity that increases levels of mutations in the viral genome. As expected, ribavirin treatment introduced mutations into the Asibi virus genome at a very high frequency and decreased viral infectivity while, in contrast, the 17D vaccine virus was resistant to ribavirin, as treatment with the antiviral introduced very few mutations into the genome, and viral infectivity was not lost. The results were confirmed for another YF wild-type parental and vaccine pair, a wild-type French viscerotropic virus and French neurotropic vaccine. Using recombinant Asibi and 17D viruses, ribavirin sensitivity was located to viral nonstructural genes. Thus, two live-attenuated YF vaccine viruses are genetically stable even under intense mutagenic pressure, suggesting that attenuation of live-attenuated YF vaccines is due, at least in part, to fidelity of the replication complex resulting in high genetic stability.IMPORTANCE Live-attenuated viral vaccines are highly safe and efficacious but represent complex and often multigenic attenuation mechanisms. Most of these vaccines have been generated empirically by serial passaging of a wild-type (WT) virus in cell culture. One of the safest and most effective live-attenuated vaccines is yellow fever (YF) virus strain 17D, which has been used for over 80 years to control YF disease. The availability of the WT parental strain of 17D, Asibi virus, and large quantities of clinical data showing the effectiveness of the 17D vaccine make this WT parent/vaccine pair an excellent model for investigating RNA virus attenuation. Here, we investigate a mechanism of 17D attenuation and show that the vaccine virus is resistant to the antiviral compound ribavirin. The findings suggest that attenuation is in part due to a low probability of reversion or mutation of the vaccine virus genome to WT, thus maintaining a stable genotype despite external pressures.


Subject(s)
Vaccines, Attenuated/immunology , Yellow Fever Vaccine/immunology , Yellow Fever/virology , Yellow fever virus/immunology , Animals , Antiviral Agents/therapeutic use , Genetic Variation/genetics , Humans , Polymorphism, Single Nucleotide/genetics , Ribavirin/therapeutic use
12.
mBio ; 10(5)2019 09 17.
Article in English | MEDLINE | ID: mdl-31530669

ABSTRACT

Zika virus (ZIKV) is a flavivirus that is structurally highly similar to the related viruses, dengue virus (DENV), West Nile virus, and yellow fever virus. ZIKV causes an acute infection that often results in mild symptoms but that can cause severe disease in rare instances. Following infection, individuals mount an adaptive immune response, composed of antibodies (Abs) that target the envelope (E) glycoprotein of ZIKV, which covers the surface of the virus. Groups have studied monoclonal antibodies and polyclonal immune sera isolated from individuals who recovered from natural ZIKV infections. Some of these antibodies bind to domain III of E (EDIII), but the functional importance of these antibodies is unknown. In this study, we aimed to determine if EDIII is a major target of the potent serum neutralizing antibodies present in people after ZIKV infection. By generating a chimeric virus containing ZIKV EDIII in a DENV4 virus backbone, our data show a minor role of EDIII-targeting antibodies in human polyclonal neutralization. These results reveal that while monoclonal antibody (MAb) studies are informative in identifying individual antibody epitopes, they can overestimate the importance of epitopes contained within EDIII as targets of serum neutralizing antibodies. Additionally, these results argue that the major target of human ZIKV neutralizing antibodies resides elsewhere in E; however, further studies are needed to assess the epitope specificity of the neutralizing response at the population level. Identification of the major epitopes on the envelope of ZIKV recognized by serum neutralizing antibodies is critical for understanding protective immunity following natural infection and for guiding the design and evaluation of vaccines.IMPORTANCE Zika virus is a flavivirus that was recently introduced to Latin America, where it caused a massive epidemic. Individuals infected with ZIKV generate an immune response composed of antibodies which bind to the envelope (E) protein. These anti-E antibodies are critical in protecting individuals from subsequent infection. Multiple groups have found that many ZIKV antibodies bind to domain III of E (EDIII), suggesting that this region is an important target of neutralizing antibodies. Here, we generated a chimeric virus containing ZIKV EDIII in a dengue virus backbone to measure ZIKV EDIII-specific antibody responses. We found that while polyclonal ZIKV immune serum contains antibodies targeting EDIII, they constitute only a small fraction of the total population of antibodies that neutralize ZIKV. Further studies are needed to define the main targets on the viral envelope recognized by human neutralizing antibodies, which is critical for guiding the development of ZIKV vaccines.

13.
Expert Rev Vaccines ; 18(8): 867-875, 2019 08.
Article in English | MEDLINE | ID: mdl-31269829

ABSTRACT

Background: The World Health Organization recommends use of a single yellow fever (YF) vaccine dose for life and fractional doses in outbreaks when there are limited vaccine stocks. In endemic regions, this vaccine is given as part of routine infant immunization programs around 9 months of age. There is a need to better understand immune responses when vaccinating infants particularly in contexts where the child may be malnourished. Methods: Data from 393 Malian and Ghanaian infants who concomitantly received measles and YF vaccines at 9 to 11 months of age were retrospectively analyzed. Response to YF vaccine was examined for association with nutritional status at time of vaccination, sex, age, pre-vaccination titers and season of vaccination. Results: Neutralizing antibodies following vaccination were unaffected by season of vaccination, sex, pre-vaccination titers or nutritional status, though there was a trend to higher titers in males and children with higher height for age z-scores. Seroconversion rates differed significantly between countries (63.5 in Ghana vs. 91.0% in Mali). Conclusion: Longitudinal, prospective studies are needed to optimize the use of YF vaccine in infants in endemic settings. There may be a need for booster vaccinations and to compare various vaccine preparations to optimize the use of available vaccines.

15.
Nat Med ; 25(8): 1218-1224, 2019 08.
Article in English | MEDLINE | ID: mdl-31308506

ABSTRACT

Flaviviral infections result in a wide spectrum of clinical outcomes, ranging from asymptomatic infection to severe disease. Although the correlates of severe disease have been explored1-4, the pathophysiology that differentiates symptomatic from asymptomatic infection remains undefined. To understand the molecular underpinnings of symptomatic infection, the blood transcriptomic and metabolomic profiles of individuals were examined before and after inoculation with the live yellow fever viral vaccine (YF17D). It was found that individuals with adaptive endoplasmic reticulum (ER) stress and reduced tricarboxylic acid cycle activity at baseline showed increased susceptibility to symptomatic outcome. YF17D infection in these individuals induced maladaptive ER stress, triggering downstream proinflammatory responses that correlated with symptomatic outcome. The findings of the present study thus suggest that the ER stress response and immunometabolism underpin symptomatic yellow fever and possibly even other flaviviral infections. Modulating either ER stress or metabolism could be exploited for prophylaxis against symptomatic flaviviral infection outcome.


Subject(s)
Endoplasmic Reticulum Stress , Yellow Fever Vaccine/immunology , Yellow Fever/metabolism , Adult , Citric Acid Cycle , Disease Susceptibility , Humans , Middle Aged , Reactive Oxygen Species/metabolism , Vaccines, Attenuated/immunology , Yellow Fever/etiology
16.
Curr Opin Infect Dis ; 32(5): 390-393, 2019 10.
Article in English | MEDLINE | ID: mdl-31335440

ABSTRACT

PURPOSE OF REVIEW: Climate change, deforestation, urbanization, and increased population mobility have made the risk of large outbreaks of yellow fever more likely than ever. Yellow fever vaccine production barely meets demands. In this review, we address the causes of the recent yellow fever outbreaks, why fractional dose yellow fever vaccination works, the role of virus neutralizing antibodies in the protection against yellow fever, and the need for revaccination. RECENT FINDINGS: Human activities have profoundly changed the epidemiology of yellow fever. The excess of infectious viral particles in routine yellow fever vaccine batches allows for off-label use of fractional dose yellow fever vaccination in response to emergency situations. Two studies have confirmed long-term protection after fractional dose yellow fever vaccination. The need for the presence of virus neutralizing antibodies (VNA) to protect an individual against yellow fever depends on the epidemiological setting. In case of sylvatic transmission, population immunity is irrelevant for individual protection, as mosquitoes are transmitting the virus from infected nonhuman primates to human. SUMMARY: With the growing connectivity through air travel, countries with high densities of nonimmune populations and of the urban mosquito vector, Aedes aegypti, should ensure that their citizens are properly vaccinated against yellow fever before traveling to a yellow fever endemic country. In the situation of sylvatic transmission, the presence of protective levels of VNA will determine the outcome and may require revaccination at some point in time.

17.
Vaccine ; 37(27): 3580-3587, 2019 Jun 12.
Article in English | MEDLINE | ID: mdl-31122859

ABSTRACT

Dengue virus (DENV) infection is a global health threat with the potential to affect at least 3.6 billion people living in areas of risk. No specific curative treatments against dengue disease are available and vaccines are currently the only way to prevent the disease. The tetravalent dengue vaccine developed by Sanofi Pasteur has demonstrated significant efficacy in phase III studies and is now licensed in several countries for the prevention of disease in dengue-seropositives over 9 years of age. The vaccine is composed of four recombinant, live, attenuated vaccines (CYD 1-4) based on a yellow fever vaccine 17D (YFV 17D) backbone, each expressing the pre-membrane (prM) and envelope (E) genes of one of the four DENV serotypes. Virus maturity could impact the biological activity of the vaccine viruses. To address this question, the maturity of the four vaccine viruses used in phase III clinical studies was assessed by two complementary techniques: mass spectrometry (MS) and cryo-electron microscopy (cryoEM). MS assessed viral maturity at the molecular level by quantifying specifically the prM, and M proteins. CryoEM provided information at the particle level, allowing visualizing the different phenotypes of viral particles: spiky (immature), smooth/bumpy (mature), and mixed (partially mature). Results of the two assays used in this study show that all four CYD dengue vaccine viruses present in lots used in phase III efficacy trials, display in the majority a mature phenotype.

18.
Vaccine ; 37(24): 3214-3220, 2019 May 27.
Article in English | MEDLINE | ID: mdl-31047674

ABSTRACT

Yellow fever (YF) is a high-lethality viral disease, endemic in tropical regions of South America and Africa, with a population of over 900 million people under risk. A highly effective attenuated vaccine, produced in embryonated eggs, has been used for about 80 years. However, egg-based production limits manufacturing capacity, and vaccine shortage led to the emergency use of a fractional dose (1/5) by the WHO in an outbreak in Africa in 2016 and by Brazilian authorities during an outbreak in 2018. In addition, rare but fatal adverse events of this vaccine have been reported since 2001. These two aspects make clear the need for the development of a new vaccine. In an effort to develop an inactivated YF vaccine, Bio-Manguinhos/FIOCRUZ started developing a new vaccine based on the production of the attenuated 17DD virus in serum-free conditions in Vero cells propagated in bioreactors, followed by chromatography-based purification and ß-propiolactone inactivation. Virus purification was studied in this work. Capture was performed using an anion-exchange membrane adsorber (Sartobind® Q), resulting in a virus recovery of 80.2 ±â€¯4.8% and a residual DNA level of 1.3 ±â€¯1.6 ng/dose, thus in accordance with the recommendations of the WHO (<10 ng/dose). However, the level of host cell proteins (HCP) was still high for a human vaccine, so a second chromatography step was developed based on a multimodal resin (Capto™ Core 700). This step resulted in a virus recovery of 65.7 ±â€¯4.8% and decreased HCP levels to 345 ±â€¯25 ppm. The overall virus recovery in these chromatography steps was 52.7%. SDS-PAGE of the purified sample showed a band with molecular mass of 56 kDa, thus consistent with the virus envelope protein (E) and corresponding to 96.7% of identified proteins. A Western blot stained with an antibody against the E protein showed a single band, confirming the identity of the sample.

19.
J Travel Med ; 26(6)2019 Sep 02.
Article in English | MEDLINE | ID: mdl-30937437

ABSTRACT

Rationale for review: The global yellow fever vaccine supply is insufficient to provide full-dose vaccination to millions threatened by outbreaks. Given the excess of live-attenuated 17D yellow fever virus in the current single dose vials, dose sparing would increase available vaccine doses manifold. Fractional-dose yellow fever vaccination is now accepted as an emergency solution, as short-term protection has been confirmed in an outbreak situation in the Democratic Republic of Congo, but broader application of this dose-sparing strategy is still not recommended. In this review, important knowledge gaps that hamper this application such as long-term protection after fractional-dose vaccination, safety, comparability across different genetic backgrounds and different World Health Organization-licensed yellow fever vaccines and immunogenicity in infants are addressed.Main findings: Recently, published results on long-term protection after fractional-dose vaccination in healthy young volunteers indicate that if a person mounts a protective response shortly after vaccination, the protective response will persist for 10 years and possibly longer. It also appears that fractional-dose vaccination does not elicit more serious adverse events than standard dose vaccination. Short-term immunogenicity studies are currently underway in specific populations (infants, human immunodeficiency virus (HIV)-infected persons and healthy adults living in Uganda and Kenya), of which the results will become available in 2021-22.Conclusions: Available results on long-lasting immunogenicity of fractional-dose yellow fever vaccination are encouraging, although confirmation is required in larger populations including young children living in yellow fever endemic areas.

20.
Theory Biosci ; 138(2): 223-239, 2019 Nov.
Article in English | MEDLINE | ID: mdl-30740641

ABSTRACT

Dengue is, in terms of death and economic cost, one of the most important infectious diseases in the world. So, its mathematical modeling can be a valuable tool to help us to understand the dynamics of the disease and to infer about its spreading by the proposition of control methods. In this paper, control strategies, which aim to eliminate the Aedes aegypti mosquito, as well as proposals for the vaccination campaign are evaluated. In our mathematical model, the mechanical control is accomplished through the environmental support capacity affected by a discrete function that represents the removal of breedings. Chemical control is carried out using insecticide and larvicide. The efficiency of vaccination is studied through the transfer of a fraction of individuals, proportional to the vaccination rate, from the susceptible to the recovered compartments. Our major find is that the dengue fever epidemic is only eradicated with the use of an immunizing vaccine because control measures, directed against its vector, are not enough to halt the disease spreading. Even when the infected mosquitoes are eliminated from the system, the susceptible ones are still present, and infected humans cause dengue fever to reappear in the human population.


Subject(s)
Dengue Vaccines/therapeutic use , Dengue/epidemiology , Dengue/prevention & control , Epidemics , Vaccination , Aedes , Animals , Climate , Computer Simulation , Culicidae , Humans , Insecticides/pharmacology , Models, Theoretical , Mosquito Vectors , Oviposition/drug effects , Probability , Temperature
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