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BACKGROUND: Butantan-Dengue Vaccine (Butantan-DV) is an investigational, single-dose, live, attenuated, tetravalent vaccine against dengue disease, but data on its overall efficacy are needed. METHODS: In an ongoing phase 3, double-blind trial in Brazil, we randomly assigned participants to receive Butantan-DV or placebo, with stratification according to age (2 to 6 years, 7 to 17 years, and 18 to 59 years); 5 years of follow-up is planned. The objectives of the trial were to evaluate overall vaccine efficacy against symptomatic, virologically confirmed dengue of any serotype occurring more than 28 days after vaccination (the primary efficacy end point), regardless of serostatus at baseline, and to describe safety up to day 21 (the primary safety end point). Here, vaccine efficacy was assessed on the basis of 2 years of follow-up for each participant, and safety as solicited vaccine-related adverse events reported up to day 21 after injection. Key secondary objectives were to assess vaccine efficacy among participants according to dengue serostatus at baseline and according to the dengue viral serotype; efficacy according to age was also assessed. RESULTS: Over a 3-year enrollment period, 16,235 participants received either Butantan-DV (10,259 participants) or placebo (5976 participants). The overall 2-year vaccine efficacy was 79.6% (95% confidence interval [CI], 70.0 to 86.3) - 73.6% (95% CI, 57.6 to 83.7) among participants with no evidence of previous dengue exposure and 89.2% (95% CI, 77.6 to 95.6) among those with a history of exposure. Vaccine efficacy was 80.1% (95% CI, 66.0 to 88.4) among participants 2 to 6 years of age, 77.8% (95% CI, 55.6 to 89.6) among those 7 to 17 years of age, and 90.0% (95% CI, 68.2 to 97.5) among those 18 to 59 years of age. Efficacy against DENV-1 was 89.5% (95% CI, 78.7 to 95.0) and against DENV-2 was 69.6% (95% CI, 50.8 to 81.5). DENV-3 and DENV-4 were not detected during the follow-up period. Solicited systemic vaccine- or placebo-related adverse events within 21 days after injection were more common with Butantan-DV than with placebo (58.3% of participants, vs. 45.6%). CONCLUSIONS: A single dose of Butantan-DV prevented symptomatic DENV-1 and DENV-2, regardless of dengue serostatus at baseline, through 2 years of follow-up. (Funded by Instituto Butantan and others; DEN-03-IB ClinicalTrials.gov number, NCT02406729, and WHO ICTRP number, U1111-1168-8679.).
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Vacinas contra Dengue , Vírus da Dengue , Dengue , Vacinas Atenuadas , Adulto , Criança , Pré-Escolar , Humanos , Anticorpos Antivirais , Dengue/prevenção & controle , Vacinas contra Dengue/efeitos adversos , Vacinas contra Dengue/uso terapêutico , Vírus da Dengue/imunologia , Método Duplo-Cego , Vacinação , Vacinas , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/uso terapêutico , Brasil , Eficácia de Vacinas , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , SeguimentosRESUMO
Ebola virus disease (EVD) caused by Ebola virus (EBOV) is a severe, often fatal, hemorrhagic disease. A critical component of the public health response to curb EVD epidemics is the use of a replication-competent, recombinant vesicular stomatitis virus (rVSV)-vectored Ebola vaccine, rVSVΔG-ZEBOV-GP (ERVEBO). In this Gem, we will discuss the past and ongoing development of rVSVΔG-ZEBOV-GP, highlighting the importance of basic science and the strength of public-private partnerships to translate fundamental virology into a licensed VSV-vectored Ebola vaccine.
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Vacinas contra Ebola , Ebolavirus , Vetores Genéticos , Doença pelo Vírus Ebola , Vesiculovirus , Humanos , Vacinas contra Ebola/genética , Vacinas contra Ebola/imunologia , Ebolavirus/genética , Ebolavirus/imunologia , Vetores Genéticos/genética , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Vesiculovirus/genética , Parcerias Público-PrivadasRESUMO
BACKGROUND: The rVSVΔG-ZEBOV-GP vaccine (ERVEBO®) is a single-dose, live-attenuated, recombinant vesicular stomatitis virus vaccine indicated for the prevention of Ebola virus disease (EVD) caused by Zaire ebolavirus in individuals 12 months of age and older. METHODS: The Partnership for Research on Ebola VACcination (PREVAC) is a multicenter, phase 2, randomized, double-blind, placebo-controlled trial of 3 vaccine strategies in healthy children (ages 1-17) and adults, with projected 5 years of follow-up (NCT02876328). Using validated assays (GP-ELISA and PRNT), we measured antibody responses after 1-dose rVSVΔG-ZEBOV-GP, 2-dose rVSVΔG-ZEBOV-GP (given on Day 0 and Day 56), or placebo. Furthermore, we quantified vaccine virus shedding in a subset of children's saliva using RT-PCR. RESULTS: In total, 819 children and 783 adults were randomized to receive rVSVΔG-ZEBOV-GP (1 or 2 doses) or placebo. A single dose of rVSVΔG-ZEBOV-GP increased antibody responses by Day 28 that were sustained through Month 12. A second dose of rVSVΔG-ZEBOV-GP given on Day 56 transiently boosted antibody concentrations. In vaccinated children, GP-ELISA titers were superior to placebo and non-inferior to vaccinated adults. Vaccine virus shedding was observed in 31.7% of children, peaking by Day 7, with no shedding observed after Day 28 post-dose 1 or any time post-dose 2. CONCLUSIONS: A single dose of rVSVΔG-ZEBOV-GP induced robust antibody responses in children that was non-inferior to the responses induced in vaccinated adults. Vaccine virus shedding in children was time-limited and only observed after the first dose. Overall, these data support the use of rVSVΔG-ZEBOV-GP for the prevention of EVD in at-risk children. Clinical Trials Registration. The study is registered at ClinicalTrials.gov (NCT02876328), the Pan African Clinical Trials Registry (PACTR201712002760250), and the European Clinical Trials Register (EudraCT number: 2017-001798-18).
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Vacinas contra Ebola , Ebolavirus , Doença pelo Vírus Ebola , Adulto , Criança , Humanos , Anticorpos Antivirais , Proteínas do Envelope Viral , Vacinas Sintéticas , Vacinação/métodos , Vacinas Atenuadas , Imunogenicidade da VacinaRESUMO
BACKGROUND: This double-blind study assessed immunogenicity, lot consistency, and safety of recombinant vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSVΔG-ZEBOV-GP). METHODS: Healthy adults (N = 1197) were randomized 2:2:2:2:1 to receive 1 of 3 consistency lots of rVSVΔG-ZEBOV-GP (2 × 107 plaque-forming units [pfu]), high-dose 1 × 108 pfu, or placebo. Antibody responses pre-/postvaccination (28 days, 6 months; in a subset [n = 566], months 12, 18, and 24) were measured. post hoc analysis of risk factors associated with arthritis following vaccination was performed. RESULTS: ZEBOV-GP enzyme-linked immunosorbent assay (ELISA) geometric mean titers (GMTs) increased postvaccination in all rVSVΔG-ZEBOV-GP groups by 28 days (>58-fold) and persisted through 24 months. The 3 manufacturing lots demonstrated equivalent immunogenicity at 28 days. Neutralizing antibody GMTs increased by 28 days in all rVSVΔG-ZEBOV-GP groups, peaking at 18 months with no decrease through 24 months. At 28 days, ≥94% of vaccine recipients seroresponded (ZEBOV-GP ELISA, ≥2-fold increase, titer ≥200 EU/mL), with responses persisting at 24 months in ≥91%. Female sex and a history of arthritis were identified as potential risk factors for the development of arthritis postvaccination. CONCLUSIONS: Immune responses to rVSVΔG-ZEBOV-GP persisted to 24 months. Immunogenicity and safety results support continued rVSVΔG-ZEBOV-GP development. CLINICAL TRIALS REGISTRATION: NCT02503202.
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Vacinas contra Ebola/efeitos adversos , Ebolavirus/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Imunogenicidade da Vacina/imunologia , Vacinação , Adulto , Anticorpos Neutralizantes/análise , Anticorpos Antivirais/análise , Método Duplo-Cego , Vacinas contra Ebola/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Voluntários Saudáveis , Doença pelo Vírus Ebola/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do Tratamento , Proteínas do Envelope Viral/imunologiaRESUMO
BACKGROUND: A single-dose dengue vaccine that protects individuals across a wide age range and regardless of dengue serostatus is an unmet need. We assessed the safety and efficacy of the live, attenuated, tetravalent Butantan-dengue vaccine (Butantan-DV) in adults, adolescents, and children. We previously reported the primary and secondary efficacy and safety endpoints in the initial 2 years of follow-up. Here we report the results through an extended follow-up period, with an average of 3·7 years of follow-up. METHODS: In this double-blind, randomised, placebo-controlled, phase 3, multicentre trial in Brazil, healthy participants (aged 2-59 years) who had not previously received a dengue vaccine were enrolled and randomly assigned 2:1 (stratified by age 18-59 years, 7-17 years, and 2-6 years) using a central electronic randomisation system to receive 0·5 mL of Butantan-DV (containing approximately 103 plaque-forming units of each of the four vaccine virus strains) or placebo, administered subcutaneously. Syringes containing vaccine or placebo were prepared by an unmasked trial pharmacist who was not involved in any subsequent participant assessments; other site staff and the participants remained unaware of the group allocations. Vaccine efficacy was calculated with the accrual of virologically confirmed dengue (VCD) cases (by RT-PCR) at least 28 days after vaccination up until the cutoff (at least 2 years of follow-up from the last participant enrolled). The primary endpoint was vaccine efficacy against VCD after day 28 by any dengue virus (DENV) serotype regardless of dengue serostatus at baseline in the per-protocol population. The primary and secondary safety endpoints up until day 21 were previously reported; secondary safety endpoints include the frequency of unsolicited vaccine-related adverse events after day 22. Safety analyses were done on all participants as treated. This trial is registered with ClinicalTrials.gov (NCT02406729) and is ongoing. FINDINGS: Of 16â363 participants assessed for eligibility, 16â235 were randomly assigned between Feb 22, 2016, and July 5, 2019, and received single-dose Butantan-DV (10â259 participants) or placebo (5976 participants). 16â162 participants (Butantan-DV n=10â215; placebo n=5947) were included in the per-protocol population and 16â235 (Butantan-DV n=10â259; placebo n=5976) in the safety population. At the data cutoff (July 13, 2021), participants had 2-5 years of follow-up (mean 3·7 years [SD 1·0], median 4·0 years [IQR 3·2-4·5]). 356 VCD cases were captured through the follow-up (128 in the vaccine group and 228 in the placebo group). Vaccine efficacy against VCD caused by any DENV serotype was 67·3% (95% CI 59·4-73·9); cases caused by DENV-3 or DENV-4 were not observed. The proportions of participants who had serious adverse events were similar between treatment groups (637 [6·2%] in the vaccine group and 395 [6·6%] in the placebo group) up until the cutoff. INTERPRETATION: A single dose of Butantan-DV was generally well tolerated and efficacious against symptomatic VCD (caused by DENV-1 and DENV-2) for a mean of 3·7 years. These findings support the continued development of Butantan-DV to prevent dengue disease in children, adolescents, and adults regardless of dengue serostatus. FUNDING: Instituto Butantan and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. TRANSLATIONS: For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.
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The 2013 Ebola epidemic in Central and West Africa heralded the emergence of wide-spread, highly pathogenic viruses. The successful recombinant vector vaccine against Ebola (rVSVΔG-ZEBOV-GP) will limit future outbreaks, but identifying mechanisms of protection is essential to protect the most vulnerable. Vaccine-induced antibodies are key determinants of vaccine efficacy, yet the mechanism by which vaccine-induced antibodies prevent Ebola infection remains elusive. Here, we exploit a break in long-term vaccine efficacy in non-human primates to identify predictors of protection. Using unbiased humoral profiling that captures neutralization and Fc-mediated functions, we find that antibodies specific for soluble glycoprotein (sGP) drive neutrophil-mediated phagocytosis and predict vaccine-mediated protection. Similarly, we show that protective sGP-specific monoclonal antibodies have elevated neutrophil-mediated phagocytic activity compared with non-protective antibodies, highlighting the importance of sGP in vaccine protection and monoclonal antibody therapeutics against Ebola virus.
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Vacinas contra Ebola , Ebolavirus , Doença pelo Vírus Ebola , Animais , Glicoproteínas , Anticorpos Antivirais , Primatas , Anticorpos Monoclonais , Vacinas SintéticasRESUMO
BACKGROUND: ERVEBO®, a live recombinant vesicular stomatitis virus (VSV) vaccine containing the Zaire ebolavirus glycoprotein (GP) in place of the VSV GP (rVSVΔG-ZEBOV-GP), was advanced through clinical development by Merck & Co., Inc., Rahway, NJ, USA in collaboration with multiple partners to prevent Ebola virus disease (EVD) and has been approved for human use in several countries. METHODS: We evaluated data from three Phase 2/3 clinical trials conducted in Liberia (PREVAIL), Guinea (FLW), and Sierra Leone (STRIVE) during the 2013-2016 West African EVD outbreak to assess immune responses using validated assays. We performed a post hoc analysis of the association of vaccine response with sex, age (18-50 yrs & >50 yrs), and baseline (BL) GP-enzyme-linked immunosorbent assay (ELISA) titer (<200 & ≥200 EU/mL), including individual study (PREVAIL, FLW, or STRIVE) data and pooled data from all 3 studies. The endpoints were total IgG antibody response (EU/mL) measured by the GP-ELISA and neutralizing antibody response measured by the plaque reduction neutralization test (PRNT) to rVSVΔG-ZEBOV-GP at Days 28, 180, and 365 postvaccination. RESULTS: In the overall pooled population, in all subgroups, and in each trial independently, GP-ELISA and PRNT geometric mean titers increased from BL, generally peaking at Day 28 and persisting through Day 365. Immune responses were greater in women and participants with BL GP-ELISA ≥ 200 EU/mL, but did not differ across age groups. CONCLUSION: These data demonstrate that rVSVΔG-ZEBOV-GP elicits a robust and durable immune response through 12 months postvaccination in participants regardless of age, sex, or BL GP-ELISA titer. The higher immune responses observed in women and participants with pre-existing immunity are consistent with those described previously and for other vaccines. Trials were registered as follows: PREVAIL: ClinicalTrials.gov NCT02344407; FLW: Pan African Clinical Trials Registry PACTR201503001057193; STRIVE: ClinicalTrials.gov NCT02378753. Protocols V920-009, 011, and 018.
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Vacinas contra Ebola , Ebolavirus , Doença pelo Vírus Ebola , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Anticorpos Neutralizantes , Anticorpos Antivirais , Ensaio de Imunoadsorção Enzimática , Glicoproteínas , Doença pelo Vírus Ebola/epidemiologia , Imunogenicidade da Vacina , Imunoglobulina G , Proteínas do Envelope ViralRESUMO
Dengue (DENV) is a mosquito-borne virus with four serotypes causing substantial morbidity in tropical and subtropical areas worldwide. V181 is an investigational, live, attenuated, quadrivalent dengue vaccine. In this phase 1 double-blind, placebo-controlled study, the safety, tolerability, and immunogenicity of V181 in baseline flavivirus-naïve (BFN) and flavivirus-experienced (BFE) healthy adults were evaluated in two formulations: TV003 and TV005. TV005 contains a 10-fold higher DENV2 level than TV003. Two-hundred adults were randomized 2:2:1 to receive TV003, TV005, or placebo on Days 1 and 180. Immunogenicity against the 4 DENV serotypes was measured using a Virus Reduction Neutralization Test (VRNT60) after each vaccination and out to 1 year after the second dose. There were no discontinuations due to adverse events (AE) or serious vaccine-related AEs in the study. Most common AEs after TV003 or TV005 were headache, rash, fatigue, and myalgia. Tri- or tetravalent vaccine-viremia was detected in 63.9% and 25.6% of BFN TV003 and TV005 participants, respectively, post-dose 1 (PD1). Tri- or tetravalent dengue VRNT60 seropositivity was demonstrated in 92.6% of BFN TV003, 74.2% of BFN TV005, and 100% of BFE TV003 and TV005 participants PD1. Increases in VRNT60 GMTs were observed after the first vaccination with TV003 and TV005 in both flavivirus subgroups for all dengue serotypes, and minimal increases were measured PD2. GMTs in the TV003 and TV005 BFE and BFN groups remained above the respective baselines and placebo through 1-year PD2. These data support further development of V181 as a single-dose vaccine for the prevention of dengue disease.
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Vacinas contra Dengue , Vírus da Dengue , Dengue , Flavivirus , Adulto , Anticorpos Antivirais , Dengue/prevenção & controle , Método Duplo-Cego , Humanos , Imunogenicidade da Vacina , Vacinas Atenuadas , Vacinas CombinadasRESUMO
This review describes key aspects of the development of the rVSVΔG-ZEBOV-GP Ebola vaccine and key activities which are continuing to further expand our knowledge of the product. Extensive partnerships and innovative approaches were used to address the various challenges encountered during this process. The rVSVΔG-ZEBOV-GP Ebola vaccine was initially approved by the European Medicines Agency and prequalified by the World Health Organization in November 2019. It was approved by the United States Food and Drug Administration in December 2019 and approved in five African countries within 90 days of prequalification. The development resulted in the first stockpile of a registered Ebola vaccine that is available to support outbreak response. This also provides insights into how the example of rVSVΔG-ZEBOV-GP can inform the development of vaccines for Sudan ebolavirus, Marburg virus, and other emerging epidemic diseases in terms of the types of approaches and data needed to support product registration, availability, and the use of a filovirus vaccine.
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Preventative vaccines are considered one of the most cost-effective and efficient means to contain outbreaks and prevent pandemics. However, the requirements to gain licensure and manufacture a vaccine for human use are complex, costly, and time-consuming. The 2013-2016 Ebola virus disease (EVD) outbreak was the largest EVD outbreak to date and the third Public Health Emergency of International Concern in history, so to prevent a pandemic, numerous partners from the public and private sectors combined efforts and resources to develop an investigational Zaire ebolavirus (EBOV) vaccine candidate (rVSVΔG-ZEBOV-GP) as quickly as possible. The rVSVΔG-ZEBOV-GP vaccine was approved as ERVEBOTM by the European Medicines Authority (EMA) and the United States Food and Drug Administration (FDA) in December 2019 after five years of development. This review describes the development program of this EBOV vaccine, summarizes what is known about safety, immunogenicity, and efficacy, describes ongoing work in the program, and highlights learnings applicable to the development of pandemic vaccines.
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BACKGROUND: Establishment of immune correlates of protection can provide a measurable criterion for assessing protection against infection or disease. For some vaccines, such as the measles vaccine, antibodies serve as the correlate of protection, but for others, such as human papillomavirus, the correlate of protection remains unknown. Merck & Co, Kenilworth, NJ, USA, in collaboration with multiple partners, developed a live recombinant vesicular stomatitis virus vaccine (rVSVΔG-ZEBOV-GP [ERVEBO]) containing the Zaire ebolavirus glycoprotein (GP) in place of the recombinant vesicular stomatitis virus GP to prevent Ebola virus disease. Seroresponse, defined as post-vaccination GP-ELISA of 200 ELISA units (EU) per mL or higher and two-times or more above baseline, was proposed; however, correlates of protection have not been determined. The objective of this post-hoc analysis was to infer possible correlates of protection for rVSVΔG-ZEBOV-GP. METHODS: In this post-hoc analysis we included vaccinated participants with serology data from three phase 2/3 immunogenicity trials in Guinea, Sierra Leone, and Liberia (n=2199). Two of the trials were open-label, single-arm trials (one randomised [STRIVE], one non-randomised [FLW]); and one trial was randomised, placebo-controlled with two vaccine comparators (PREVAIL). Endpoints were total IgG antibody response (EU per mL) to rVSVΔG-ZEBOV-GP measured by GP-ELISA and neutralising antibody response to rVSVΔG-ZEBOV-GP measured by plaque reduction neutralisation test at days 14, 28, 180, and 365 after vaccination. Reverse cumulative distribution curves of the antibody concentrations were used to estimate statistical correlates of protection between 70% and 100% that might be applied to vaccine efficacy and effectiveness estimates. FINDINGS: Although GP-ELISA and plaque reduction neutralisation tests showed similar response patterns, GP-ELISA provided a wider range of measurable titres and better differentiation for estimating correlates of protection compared with the plaque reduction neutralisation test. At day 14 after vaccination in the FLW trial, 1060 (100%) of 1060 participants had GP-ELISA levels at or above 68 EU per mL and 742 (70%) of 1060 had levels at or above 313 EU per mL. At day 28 after vaccination in the pooled population, 1953 (100%) of 1953 participants had levels at or above 73 EU per mL and 1368 (70%) of 1953 participants had levels at or above 735 EU per mL. GP-ELISA seroresponse 200 EU per mL or higher and two-times or more increase in antibody level from baseline occurred in 80% or higher of participants at each assessment and in 94% or higher of participants at any time after vaccination. INTERPRETATION: Our results are consistent with previous work suggesting that seroresponse defined as GP-ELISA of 200 EU per mL or higher and two-times or more from baseline associated with vaccination might be the most appropriate dichotomous correlate of protection and falls within the seroprotective threshold range described herein. FUNDING: Merck Sharp & Dohme, Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, US Department of Health and Human Services.
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Vacinas contra Ebola , Ebolavirus , Estomatite Vesicular , Anticorpos Antivirais , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , República Democrática do Congo , Glicoproteínas , HumanosRESUMO
ABSTRACTThe recent impact of Ebola virus disease (EVD) on public health in Africa clearly demonstrates the need for a safe and efficacious vaccine to control outbreaks and mitigate its threat to global health. ERVEBO® is an effective recombinant Vesicular Stomatitis Virus (VSV)-vectored Ebola virus vaccine (VSV-EBOV) that was approved by the FDA and EMA in late 2019 for use in prevention of EVD. Since the parental virus VSV, which was used to construct VSV-EBOV, is pathogenic for livestock and the vaccine virus may be shed at low levels by vaccinated humans, widespread deployment of the vaccine requires investigation into its infectivity and transmissibility in VSV-susceptible livestock species. We therefore performed a comprehensive clinical analysis of the VSV-EBOV vaccine virus in swine to determine its infectivity and potential for transmission. A high dose of VSV-EBOV resulted in VSV-like clinical signs in swine, with a proportion of pigs developing ulcerative vesicular lesions at the nasal injection site and feet. Uninoculated contact control pigs co-mingled with VSV-EBOV-inoculated pigs did not become infected or display any clinical signs of disease, indicating the vaccine is not readily transmissible to naïve pigs during prolonged close contact. In contrast, virulent wild-type VSV Indiana had a shorter incubation period and was transmitted to contact control pigs. These results indicate that the VSV-EBOV vaccine causes vesicular illness in swine when administered at a high dose. Moreover, the study demonstrates the VSV-EBOV vaccine is not readily transmitted to uninfected pigs, encouraging its safe use as an effective human vaccine.
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Vacinas contra Ebola/efeitos adversos , Vacinas contra Ebola/imunologia , Ebolavirus/imunologia , Estomatite Vesicular/transmissão , Estomatite Vesicular/virologia , Vírus da Estomatite Vesicular Indiana/imunologia , Vesiculovirus/imunologia , África , Animais , Chlorocebus aethiops , Ebolavirus/genética , Feminino , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/virologia , Humanos , Masculino , Modelos Animais , RNA Viral , Suínos , Vacinação/métodos , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologia , Células Vero , Vesiculovirus/genéticaRESUMO
rVSVΔG-ZEBOV-GP is a live, attenuated, recombinant vesicular stomatitis virus (rVSV)-based vaccine for the prevention of Ebola virus disease caused by Zaire ebolavirus. As a replication-competent genetically modified organism, rVSVΔG-ZEBOV-GP underwent various environmental evaluations prior to approval, the most in-depth being the environmental risk assessment (ERA) required by the European Medicines Agency. This ERA, as well as the underlying methodology used to arrive at a sound conclusion about the environmental risks of rVSVΔG-ZEBOV-GP, are described in this review. Clinical data from vaccinated adults demonstrated only infrequent, low-level shedding and transient, low-level viremia, indicating a low person-to-person infection risk. Animal data suggest that it is highly unlikely that vaccinated individuals would infect animals with recombinant virus vaccine or that rVSVΔG-ZEBOV-GP would spread within animal populations. Preclinical studies in various hematophagous insect vectors showed that these species were unable to transmit rVSVΔG-ZEBOV-GP. Pathogenicity risk in humans and animals was found to be low, based on clinical and preclinical data. The overall risk for non-vaccinated individuals and the environment is thus negligible and can be minimized further through defined mitigation strategies. This ERA and the experience gained are relevant to developing other rVSV-based vaccines, including candidates under investigation for prevention of COVID-19.
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The world is experiencing an unprecedented global pandemic of coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2). Development of new vaccines and therapeutics are important to achieve long-term prevention and control of the virus. Experience gained in the development of vaccines for Ebola virus disease provide important lessons in the regulatory, clinical, and manufacturing process that can be applied to SARS-CoV-2 and other epidemic pathogens. This report outlines the main lessons learned by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD) during development of an Ebola Zaire vaccine (ERVEBO®) and looks ahead to critical lessons beyond vaccine development. It highlights focus areas for public-private partnership and regulatory harmonization that can be directly applied to current vaccine development efforts for SARS-CoV-2, while drawing attention to the need for parallel consideration of issues beyond development that are equally important to achieve global preparedness and response goals.
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New dengue vaccines are needed to prevent this globally expanding vector-borne disease. The V180 vaccine candidate consists of four recombinant, soluble, dengue virus envelope glycoproteins and has been previously evaluated in two clinical trials for safety and immunogenicity in Flavivirus-naive participants (NCT01477580 and NCT0093642). Here, we report on a randomized, placebo-controlled, double-blind study of the safety and immunogenicity of the V180 vaccine in subjects who have previously received the live attenuated tetravalent vaccine (LATV) developed by the National Institute of Allergy and Infectious Diseases (protocol #V180-002 [CIR-301]). The study was designed to evaluate whether this recombinant subunit vaccine could boost the neutralizing antibody responses induced by dengue LATV. Twenty participants who had previously received one or two doses of dengue LATV were randomized and received a single dose of V180 nonadjuvanted (N = 8), V180 adjuvanted with Alhydrogel™ (aluminum hydroxide gel, Brenntag Biosector, Frederikssund, Denmark) (N = 8), or placebo (N = 4). Immunogenicity was measured using a plaque reduction neutralization test at days 1, 15, 28, and 180 after vaccination. In addition, vaccine safety (solicited and unsolicited adverse events) was assessed using a vaccination report card for 28 days following vaccination, and serious adverse events were captured from the time of informed consent through the final study visit at 6 months after vaccination. The results of the study demonstrate that the V180 vaccine is generally well tolerated and immunogenic in these dengue-seropositive volunteers.
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Vacinas contra Dengue/uso terapêutico , Dengue/prevenção & controle , Imunização Secundária , Adjuvantes Imunológicos/uso terapêutico , Adulto , Hidróxido de Alumínio/uso terapêutico , Anticorpos Neutralizantes/imunologia , Vírus da Dengue/imunologia , Método Duplo-Cego , Feminino , Humanos , Imunogenicidade da Vacina , Reação no Local da Injeção , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , Vacinas Atenuadas/uso terapêutico , Vacinas de Subunidades Antigênicas/uso terapêutico , Vacinas Sintéticas/uso terapêutico , Proteínas do Envelope Viral/imunologia , Adulto JovemRESUMO
There is an unmet medical need for vaccines to prevent dengue. V180 is an investigational recombinant subunit vaccine that consists of truncated dengue envelope proteins (DEN-80E) for all 4 serotypes. Three dosage levels of the tetravalent DEN-80E antigens were assessed in a randomized, placebo-controlled, Phase I dose-escalation, first-in-human proof-of-principle trial in healthy, flavivirus-naïve adults in Australia (NCT01477580). The 9 V180 formulations that were assessed included either ISCOMATRIX™ adjuvant (2 dosage levels), aluminum-hydroxide adjuvant, or were unadjuvanted, and were compared to phosphate-buffered saline placebo. Volunteers received 3 injections of assigned product on a 0, 1, 2 month schedule, and were followed for safety through 1 year after the last injection. Antibody levels were assessed at 6 time-points: enrollment, 28 days after each injection, and 6 and 12 months Postdose 3 (PD3). Of the 98 randomized participants, 90 (92%) received all 3 injections; 83 (85%) completed 1-year follow-up. Immunogenicity was measured by a qualified Focus Reduction Neutralization Test with a 50% neutralization cutoff (FRNT50). All 6 V180 formulations with ISCOMATRIX™ adjuvant showed robust immunogenicity, while the 1 aluminum-adjuvanted and 2 unadjuvanted formulations were poorly immunogenic. Geometric mean antibody titers generally declined at 6 months and 1 year PD3. All 9 V180 formulations were generally well tolerated. Formulations with ISCOMATRIX™ adjuvant were associated with more adverse events than aluminum-adjuvanted or unadjuvanted formulations.
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Vacinas contra Dengue/imunologia , Dengue/prevenção & controle , Imunogenicidade da Vacina , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Vacinas contra Dengue/administração & dosagem , Vírus da Dengue , Composição de Medicamentos , Feminino , Humanos , Esquemas de Imunização , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , Estudo de Prova de Conceito , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Adulto JovemRESUMO
The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety and characteristics of live, recombinant viral vector vaccines. A recent publication by the V3SWG described live, attenuated, recombinant vesicular stomatitis virus (rVSV) as a chimeric virus vaccine for HIV-1 (Clarke et al., 2016). The rVSV vector system is being explored as a platform for development of multiple vaccines. This paper reviews the molecular and biological features of the rVSV vector system, followed by a template with details on the safety and characteristics of a rVSV vaccine against Zaire ebolavirus (ZEBOV). The rVSV-ZEBOV vaccine is a live, replication competent vector in which the VSV glycoprotein (G) gene is replaced with the glycoprotein (GP) gene of ZEBOV. Multiple copies of GP are expressed and assembled into the viral envelope responsible for inducing protective immunity. The vaccine (designated V920) was originally constructed by the National Microbiology Laboratory, Public Health Agency of Canada, further developed by NewLink Genetics Corp. and Merck & Co., and is now in final stages of registration by Merck. The vaccine is attenuated by deletion of the principal virulence factor of VSV (the G protein), which also removes the primary target for anti-vector immunity. The V920 vaccine caused no toxicities after intramuscular (IM) or intracranial injection of nonhuman primates and no reproductive or developmental toxicity in a rat model. In multiple studies, cynomolgus macaques immunized IM with a wide range of virus doses rapidly developed ZEBOV-specific antibodies measured in IgG ELISA and neutralization assays and were fully protected against lethal challenge with ZEBOV virus. Over 20,000 people have received the vaccine in clinical trials; the vaccine has proven to be safe and well tolerated. During the first few days after vaccination, many vaccinees experience a mild acute-phase reaction with fever, headache, myalgia, and arthralgia of short duration; this period is associated with a low-level viremia, activation of anti-viral genes, and increased levels of chemokines and cytokines. Oligoarthritis and rash appearing in the second week occur at a low incidence, and are typically mild-moderate in severity and self-limited. V920 vaccine was used in a Phase III efficacy trial during the West African Ebola epidemic in 2015, showing 100% protection against Ebola Virus Disease, and it has subsequently been deployed for emergency control of Ebola outbreaks in central Africa. The template provided here provides a comprehensive picture of the first rVSV vector to reach the final stage of development and to provide a solution to control of an alarming human disease.
RESUMO
INTRODUCTION: The Ebola epidemic in West Africa from 2014 to 2016 was unique in its size, location, and duration; this article reviews the experiences and lessons learned for one vaccine candidate developed during the outbreak and discusses critical gaps that still exist today which will need to be addressed for successful end to end emerging infectious disease vaccine product development in the future. AREAS COVERED: Through the formation of numerous international partnerships, the rVSVΔG-ZEBOV-GP vaccine advanced through Phase I/II/III clinical trials which resulted in favorable Phase III efficacy results. Key lessons learned that could be used to facilitate future vaccine development efforts include sufficient preclinical work in relevant animal models, innovative partnerships created to pool resources and expertise, and 'hyper' coordination and communication among partners to build trust and ensure an adequate regulatory package needed to license a vaccine. EXPERT COMMENTARY: As evidenced by the 2014-2016 outbreak in West Africa as well as the two other most recent outbreaks in the Democratic Republic of the Congo in 2018, there is an urgent need to develop new models for emerging infection vaccine development where trusted partners come together and where the development of vaccines is a shared responsibility conducted in advance of the next crisis.
Assuntos
Vacinas contra Ebola/administração & dosagem , Doença pelo Vírus Ebola/prevenção & controle , Programas de Imunização/métodos , África Ocidental/epidemiologia , Animais , Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/prevenção & controle , Surtos de Doenças , Vacinas contra Ebola/imunologia , Epidemias , Doença pelo Vírus Ebola/epidemiologia , HumanosRESUMO
BACKGROUND: Pediatric use of pneumococcal conjugate vaccines (PCV) has been associated with significant decrease in disease burden. However, disease caused by non-vaccine serotypes has increased. Safety and immunogenicity of 15-valent PCV (PCV15) containing serotypes included in 13-valent PCV (PCV13) plus serotypes 22F and 33F were evaluated in infants (NCT01215188). METHODS: Infants received adjuvanted PCV15, nonadjuvanted PCV15, or PCV13 at 2, 4, 6, and 12-15â¯months of age. Safety was monitored for 14â¯days after each dose. Serotype-specific IgG geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured at postdose-3, predose-4, and postdose-4. RESULTS: Safety profiles were comparable across vaccination groups. At postdose-3, both PCV15 formulations were non-inferior to PCV13 for 10 of 13 shared serotypes but failed non-inferiority for 3 serotypes (6A, 6B, and 19A) based on proportion of subjects achieving IgG GMC ≥0.35⯵g/mL. Adjuvanted PCV15 and nonadjuvanted PCV15 were non-inferior to PCV13 for 11 and 8 shared serotypes, respectively, based on postdose 3 comparisons of GMC ratios. PCV15 induced higher antibodies to serotypes 3, 22F, and 33F than PCV13. CONCLUSIONS: PCV15 displayed acceptable safety profile and induced IgG and OPA to all 15 vaccine serotypes at levels comparable to PCV13 for 10 of 13 shared serotypes. Study identification: V114-003. CLINICALTRIALS.GOV identifier: NCT01215188.
Assuntos
Vacinas Pneumocócicas/efeitos adversos , Vacinas Pneumocócicas/imunologia , Vacinas Conjugadas/efeitos adversos , Vacinas Conjugadas/imunologia , Feminino , Humanos , Lactente , Masculino , Vacinas Pneumocócicas/uso terapêutico , Sorogrupo , Vacinas Conjugadas/uso terapêuticoRESUMO
The 2014-2016 Ebola outbreak caused over 28,000 cases and 11,000 deaths. Merck & Co. Inc., Kenilworth, NJ USA and NewLink Genetics are working with private and public partners to develop and license an Ebola vaccine that was evaluated extensively during the outbreak. The vaccine referred to as V920 is a recombinant vesicular stomatitis virus (rVSV) in which the VSV-G envelope glycoprotein (GP) is completely replaced by the Zaire ebolavirus GP (rVSVΔG-ZEBOV-GP). Eight Phase I and four Phase II/III clinical trials enrolling approximately 17,000 subjects were conducted in parallel to the outbreak to assess the safety, immunogenicity, and/or efficacy of V920. Immunogenicity data demonstrate that anti-GP antibodies are generally detectable by ELISA by 14days postvaccination with up to 100% seroconversion observed by 28days post dose. In addition, the results of a ring vaccination trial conducted by the WHO and their partners in Guinea suggest robust vaccine efficacy within 10days of receipt of a single dose of vaccine. The vaccine is generally well-tolerated when administered to healthy, non-pregnant adults. The development of this vaccine candidate in the context of this unprecedented epidemic has involved the close cooperation of large number of international partners and highlights what we as a public health community can accomplish when working together towards a common goal. Study identification: V920-001 to V920-012. CLINICALTRIALS.GOV identifiers: NCT02269423; NCT02280408; NCT02374385; NCT02314923; NCT02287480; NCT02283099; NCT02296983; NCT02344407; NCT02378753; NCT02503202.