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Immunogenicity and protective activity of mRNA vaccine candidates against yellow fever virus in animal models.

ABSTRACT: Despite the success of the widely used attenuated yellow fever (YF) vaccine, its global supply remains a substantial barrier to implementing vaccination campaigns in endemic regions and combating emerging epidemics. In A129 mice and rhesus macaques, we evaluated the immunogenicity and protective activity of messenger RNA (mRNA) vaccine candidates encapsulated in lipid nanoparticles, expressing the pre-membrane and envelope proteins or the non-structural protein 1 of YF virus. Vaccine constructs induced humoral and cell-mediated immune responses in mice, resulting in protection against lethal YF virus infection after passive administration of serum or splenocytes from vaccinated mice. Vaccination of macaques induced sustained high humoral and cellular immune responses for at least 5 months after the second dose. Our data demonstrate that these mRNA vaccine candidates can be considered an attractive addition to the licensed YF vaccine supply based on the induction of functional antibodies correlating with protection and T-cell responses; they could alleviate the limited supply of current YF vaccines, mitigating future YF epidemics.

SUBMITTER: Medina-Magues LG

PROVIDER: S-EPMC9984760 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Immunogenicity and protective activity of mRNA vaccine candidates against yellow fever virus in animal models.

Medina-Magües Lex G LG Mühe Janine J Jasny Edith E Medina-Magües Emily S ES Roth Nicole N Lopera-Madrid Jaime J Salas-Quinchucua Cristhian C Knuese Cole C Petsch Benjamin B Osorio Jorge E JE

NPJ vaccines 20230304 1

Despite the success of the widely used attenuated yellow fever (YF) vaccine, its global supply remains a substantial barrier to implementing vaccination campaigns in endemic regions and combating emerging epidemics. In A129 mice and rhesus macaques, we evaluated the immunogenicity and protective activity of messenger RNA (mRNA) vaccine candidates encapsulated in lipid nanoparticles, expressing the pre-membrane and envelope proteins or the non-structural protein 1 of YF virus. Vaccine constructs ...[more]

PMID: 36871059

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Project description: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.

Project description:BackgroundIn 2016, the response to a yellow fever outbreak in Angola and the Democratic Republic of Congo led to a global shortage of yellow fever vaccine. As a result, a fractional dose of the 17DD yellow fever vaccine (containing one fifth [0.1 ml] of the standard dose) was offered to 7.6 million children 2 years of age or older and nonpregnant adults in a preemptive campaign in Kinshasa. The goal of this study was to assess the immune response to the fractional dose in a large-scale campaign.MethodsWe recruited participants in four age strata at six vaccination sites. We assessed neutralizing antibody titers against yellow fever virus in blood samples obtained before vaccination and at 1 month and 1 year after vaccination, using a plaque reduction neutralization test with a 50% cutoff (PRNT50). Participants with a PRNT50 titer of 10 or higher were considered to be seropositive. Those with a baseline titer of less than 10 who became seropositive at follow-up were classified as having undergone seroconversion. Participants who were seropositive at baseline and who had an increase in the titer by a factor of 4 or more at follow-up were classified as having an immune response.ResultsAmong 716 participants who completed the 1-month follow-up, 705 (98%; 95% confidence interval [CI], 97 to 99) were seropositive after vaccination. Among 493 participants who were seronegative at baseline, 482 (98%; 95% CI, 96 to 99) underwent seroconversion. Among 223 participants who were seropositive at baseline, 148 (66%; 95% CI, 60 to 72) had an immune response. Lower baseline titers were associated with a higher probability of having an immune response (P<0.001). Among 684 participants who completed the 1-year follow-up, 666 (97%; 95% CI, 96 to 98) were seropositive for yellow fever antibody. The distribution of titers among the participants who were seronegative for yellow fever antibody at baseline varied significantly among age groups at 1 month and at 1 year (P<0.001 for both comparisons).ConclusionsA fractional dose of the 17DD yellow fever vaccine was effective at inducing seroconversion in participants who were seronegative at baseline. Titers remained above the threshold for seropositivity at 1 year after vaccination in nearly all participants who were seropositive at 1 month after vaccination. These findings support the use of fractional-dose vaccination for outbreak control. (Funded by the U.S. Agency for International Development and the Centers for Disease Control and Prevention.).

Project description:Zika virus (ZIKV) emerged as an important infectious disease agent in Brazil in 2016. Infection usually leads to mild symptoms, but severe congenital neurological disorders and Guillain-Barré syndrome have been reported following ZIKV exposure. Creating an effective vaccine against ZIKV is a public health priority. We describe the protective effect of an already licensed attenuated yellow fever vaccine (YFV, 17DD) in type-I interferon receptor knockout mice (A129) and immunocompetent BALB/c and SV-129 (A129 background) mice infected with ZIKV. YFV vaccination provided protection against ZIKV, with decreased mortality in A129 mice, a reduction in the cerebral viral load in all mice, and weight loss prevention in BALB/c mice. The A129 mice that were challenged two and three weeks after the first dose of the vaccine were fully protected, whereas partial protection was observed five weeks after vaccination. In all cases, the YFV vaccine provoked a substantial decrease in the cerebral viral load. YFV immunization also prevented hippocampal synapse loss and microgliosis in ZIKV-infected mice. Our vaccine model is T cell-dependent, with AG129 mice being unable to tolerate immunization (vaccination is lethal in this mouse model), indicating the importance of IFN-γ in immunogenicity. To confirm the role of T cells, we immunized nude mice that we demonstrated to be very susceptible to infection. Immunization with YFV and challenge 7 days after booster did not protect nude mice in terms of weight loss and showed partial protection in the survival curve. When we evaluated the humoral response, the vaccine elicited significant antibody titers against ZIKV; however, it showed no neutralizing activity in vitro and in vivo. The data indicate that a cell-mediated response promotes protection against cerebral infection, which is crucial to vaccine protection, and it appears to not necessarily require a humoral response. This protective effect can also be attributed to innate factors, but more studies are needed to strengthen this hypothesis. Our findings open the way to using an available and inexpensive vaccine for large-scale immunization in the event of a ZIKV outbreak.

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Immunogenicity and protective activity of mRNA vaccine candidates against yellow fever virus in animal models.

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Immunogenicity and protective activity of mRNA vaccine candidates against yellow fever virus in animal models.

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