Paul Chaplin's research while affiliated with Bavarian Nordic and other places
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Publications (116)
In the last decade, immunotherapy has revolutionized cancer treatment. However, the lack of potent therapy-induced immune responses against solid tumors due to the immune-suppressive tumor microenvironment (TME) is still a major drawback. One approach to reprogram TME is virotherapy, which can target tumors via destruction of infected tumor cells a...
The induction of antiviral innate immunity by systemic immunization with live virus can be employed to positively impact the response to therapeutic vaccination. We previously demonstrated that systemic immunization with a non-replicating MVA encoding CD40 ligand (CD40L) enhances innate immune cell activation and function, and triggers potent antit...
Background
The ongoing monkeypox outbreak, a WHO-declared PHEIC, requires fast and broad rollout of MVA-BN vaccinations among risk groups. An initial single-dose strategy, followed by a delayed second dose beyond the approved 4-week interval, could help managing tight vaccine resources.
Methods
Bavarian Nordic has run a study in vaccinia-naïve par...
Background
Though Modified Vaccinia Ankara - Bavarian Nordic (MVA-BN®). vaccination is approved for smallpox and monkeypox prevention, immunological persistence and booster effects remain undescribed.
Methods
Participants naïve to smallpox vaccination were randomized to 1 dose MVA-BN (1×MVA, N = 181), 2 doses MVA-BN (2×MVA, N = 183), or placebo (N...
Respiratory syncytial virus (RSV) causes a respiratory disease with a potentially fatal outcome especially in infants and elderly individuals. Several vaccines failed in pivotal clinical trials, and to date, no vaccine against RSV has been licensed. We have developed an RSV vaccine based on the recombinant Modified Vaccinia Virus Ankara-BN® (MVA-RS...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic. Here, we present non-human primate immunogenicity and protective efficacy data generated with the capsid virus-like particle (cVLP)-based vaccine ABNCoV2 that has previously demonstrated immunogenicity in mice. In rhesus macaques, a single vaccination with...
Background
There are limited data regarding immunological correlates of protection for the modified vaccinia Ankara (MVA) smallpox vaccine.
Methods
Five hundred twenty-three vaccinia-naïve subjects were randomized to receive two vaccine doses, either lyophilized MVA subcutaneously (SC), liquid MVA SC or liquid MVA intradermally (ID) 28 days apart....
Background Human cancers are extraordinarily heterogeneous in terms of tumor antigen expression, immune infiltration and composition. A common feature, however, is the host′s inability to mount potent immune responses that prevent tumor growth effectively. Often, naturally primed CD8 ⁺ T cells against solid tumors lack adequate stimulation and effi...
Background
Virus-based vaccines and appropriate costimulation potently enhance antigen-specific T cell immunity against cancer. In the present study, we exploit both innate and adaptive immune responses triggered by a novel recombinant modified vaccinia virus Ankara (rMVA) encoding a Tumor-Associated Antigen (TAA) and the costimulatory CD40L agains...
Background:
Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in young children and the elderly. Protective immunity is not generated after repeated infections, but vaccination may hopefully prove effective.
Methods:
This phase 2 clinical study investigated a multivalent RSV vaccine (MVA-BN®-RSV) designed to induce...
To the Editor: The trial of modified vaccinia Ankara (MVA) reported by Pittman et al. (Nov. 14 issue)¹ was underpowered to detect one of the most serious but underrecognized complications of the established vaccines ACAM2000 and Dryvax — myopericarditis (myocarditis and pericarditis). Studies have shown an incidence of approximately 1 case of clini...
Respiratory disease caused by RSV infection is recognized as a severe public health issue in infants, young children and elderly with no specific treatment option. Vaccination may be the most effective strategy to combat this highly infectious virus although no vaccine has been approved. The novel vaccine candidate MVA-BN-RSV encodes RSV surface pr...
Traditional replicating smallpox vaccines are associated with serious safety concerns in the general population and are contraindicated in immunocompromised individuals. However, this very population remains at greatest risk for severe complications following viral infections, making vaccine prevention particularly relevant. MVA-BN was developed as...
Background:
Many countries have stockpiled vaccines because of concerns about the reemergence of smallpox. Traditional smallpox vaccines are based on replicating vaccinia viruses; these vaccines have considerable side effects.
Methods:
To evaluate the efficacy of modified vaccinia Ankara (MVA) as a potential smallpox vaccine, we randomly assigne...
Virus-based vaccines and appropriate costimulation potently enhance antigen-specific T cell immunity against cancer. Here we report the use of recombinant modified vaccinia virus Ankara (rMVA) encoding costimulatory CD40L against solid tumors. Therapeutic treatment with rMVA-CD40L-expressing tumor-associated antigens results in the control of estab...
Background
Smallpox remains a high-priority threat due to its potential for re-emergence through events including bioterrorism and spontaneous mutation. While traditional replicating smallpox vaccines such as ACAM2000 are associated with serious side effects, the non-replicating MVA BN smallpox vaccine was developed as a safer alternative.
Methods...
Virus-based vaccines and appropriate costimulation potently enhance antigen-specific T cell immunity against cancer. In the present study, we exploit both innate and adaptive immune responses triggered by recombinant modified vaccinia virus Ankara (rMVA) encoding costimulatory CD40L against large, established tumors in different combinatory setting...
Virus-based vaccines and appropriate costimulation enhance potent antigen-specific T cell immunity against cancer. However, the tumor microenvironment exerts intrinsic and extrinsic mechanisms to evade tumor destruction. In the present study we exploit both innate and adaptive immune responses triggered by a novel recombinant modified vaccinia viru...
Background
Modified Vaccinia Ankara (MVA) is a live, viral vaccine under advanced development as a non-replicating smallpox vaccine. A randomised, double-blind, placebo-controlled phase III clinical trial was conducted to demonstrate the humoral immunogenic equivalence of three consecutively manufactured MVA production lots, and to confirm the safe...
Clinical trial protocol.
(PDF)
Patents by Paul Chaplin.
(DOCX)
CONSORT 2010 checklist.
(DOC)
Newborns are considered difficult to protect against infections shortly after birth, due to their ineffective immune system that shows quantitative and qualitative differences compared to adults. However, here we show that a single vaccination of mice at birth with a replication-deficient live vaccine Modified Vaccinia Ankara [MVA] efficiently indu...
Bacterial flagellin enhances innate and adaptive immune responses and is considered a promising adjuvant for the development of vaccines against infectious diseases and cancer. Antigen-presenting cells recognize flagellin with the extracellular TLR5 and the intracellular NLRC4 inflammasome-mediated pathway. The detailed cooperation of these innate...
The immunological outcome of infections and vaccinations is largely determined during the initial first days in which antigen-presenting cells instruct T cells to expand and differentiate into effector and memory cells. Besides the essential stimulation of the T cell receptor complex a plethora of co-stimulatory signals not only ensures a proper T...
There are currently no approved therapeutics or vaccines to treat or protect against the severe hemorrhagic fever and death caused by Ebola virus (EBOV). Ebola virus-like particles (EBOV VLPs) consisting of the matrix protein VP40, the glycoprotein (GP), and the nucleoprotein (NP) are highly immunogenic and protective in nonhuman primates against E...
CONSORT Checklist.
(DOCX)
Vaccinia-specific ELISA GMTs by Week (PPS, N = 102).
Administrations at Week 0 (Group MM: first MVA vaccination; Group PM: Placebo) and at Week 4 (Group MM: second MVA vaccination; Group PM: first MVA vaccination). No samples were taken between week 8 and 32, therefore the graph was cut. PPS = Per Protocol Set, GMT = geometric mean titer, ELISA = e...
Grade and Relationship of Unsolicited AEs.
(DOCX)
Vaccinia-specific PRNT GMTs by Week (PPS, N = 102).
Administrations at Week 0 (Group MM: first MVA vaccination; Group PM: Placebo) and at Week 4 (Group MM: second MVA vaccination; Group PM: first MVA vaccination). No samples were taken between week 8 and 32, therefore the graph was cut. PPS = Per Protocol Analysis Set, GMT = geometric mean titer, P...
Immunogenicity Results PPS.
(DOCX)
Unsolicited related AEs after second vaccination.
(DOCX)
Unsolicited related AEs after first vaccination.
(DOCX)
Unsolicited AEs ≥ 3%.
(DOCX)
Background:
Modified Vaccinia Ankara MVA-BN® is a live, highly attenuated, viral vaccine under advanced development as a non-replicating smallpox vaccine. In this Phase II trial, the safety and immunogenicity of Modified Vaccinia Ankara MVA-BN® (MVA) was assessed in a 56-80 years old population.
Methods:
MVA with a virus titer of 1 x 108 TCID50/...
Baseline Seropositivity Rates.
(DOCX)
Initial Protocol for IRBs.
(PDF)
Demographic Data PPS.
(DOCX)
Overview of Immunogenicity Results.
(DOCX)
BACKGROUND
The West African outbreak of Ebola virus disease that peaked in 2014 has caused more
than 11,000 deaths. The development of an effective Ebola vaccine is a priority for control
of a future outbreak.
METHODS
In this phase 1 study, we administered a single dose of the chimpanzee adenovirus 3
(ChAd3) vaccine encoding the surface glycoprotei...
Poxviruses produce significant amounts of double-stranded (ds)RNA late in infection due to convergent transcription of late genes, but have evolved to avoid producing dsRNA early in infection. Cellular protein kinase R (PKR) is activated by dsRNA and can trigger important antiviral defense mechanisms including protein synthesis shutdown, apoptosis...
Background:
Replicating smallpox vaccines can cause severe complications in individuals with atopic dermatitis (AD). Prior studies evaluating Modified Vaccinia Ankara virus (MVA), a non-replicating vaccine in humans, showed a favorable safety and immunogenicity profile in healthy volunteers.
Objective:
This Phase II study compared the safety and...
Background. First- and second-generation smallpox vaccines are contraindicated in individuals infected with human immunodeficiency virus (HIV). A new smallpox vaccine is needed to protect this population in the context of biodefense preparedness. The focus of this study was to compare the safety and immunogenicity of a replication-deficient, highly...
Background:
Conventional smallpox vaccines based on replicating vaccinia virus (VV) strains (e.g. Lister Elstree, NYCBOH) are associated with a high incidence of myo-/pericarditis, a severe inflammatory cardiac complication. A new smallpox vaccine candidate based on a non-replicating Modified Vaccinia Ankara (MVA) poxvirus has been assessed for ca...
Unlabelled:
Double-stranded RNA (dsRNA) is an important molecular pattern associated with viral infection and is detected by various extra- and intracellular recognition molecules. Poxviruses have evolved to avoid producing dsRNA early in infection but generate significant amounts of dsRNA late in infection due to convergent transcription of late...
Background:
Following vaccination with traditional smallpox vaccines or after exposure to vaccinated individuals, subjects with atopic dermatitis (AD) can develop eczema vaccinatum, a severe disease with disseminated eruption of pustular contagious lesions. Alternative smallpox vaccines with an improved safety profile would address this unmet medi...
Reintroduction of Variola major as an agent of bioterrorism remains a concern. Time to seroconversion and plaque reduction neutralizing antibody titers (PRNT) of 1 or 2 standard doses (SD) were compared to a single high dose (HD) of modified vaccinia Ankara (MVA).
Ninety subjects were randomized 1:1 to receive 1 HD or 2 SD of MVA subcutaneously on...
Modified vaccinia Ankara (MVA) is a safe and promising viral vaccine vector that is currently investigated in several clinical and pre-clinical trials. In contrast to inactivated or sub-unit vaccines, MVA is able to induce strong humoral as well as cellular immune responses. In order to further improve its CD8 T cell inducing capacity, we genetical...
Modified vaccinia virus Ankara (MVA) has been shown to be suitable for the generation of experimental vaccines against cancer and infectious diseases, eliciting strong humoral and cellular immune responses. In viral vectored vaccines, strong recombinant antigen expression and timing of expression influence the quantity and quality of the immune res...
The present invention provides an attenuated virus, which is derived from Modified Vaccinia Ankara virus and characterized by the loss of its capability to reproductively replicate in human cell lines. It further describes recombinant viruses derived from this virus and the use of the virus, or its recombinants, as a medicament or vaccine. A method...
Introduction:
Reintroduction of Variola major as an agent of bioterrorism remains a concern. A shortened dosing schedule of Bavarian Nordic's (BN) IMVAMUNE(®) (modified vaccinia Ankara vaccine against smallpox) was compared to the currently recommended 0- and 28-day schedule for non-inferiority by evaluating the magnitude and kinetics of the immun...
The invention relates inter alia to a method for inducing a long-term protection in an animal against foreign antigens and tumor antigens comprising the step of administering to the animal at least one factor selected from type I interferons and Flt-3, and to a method for inducing a long-term increase of the number of dendritic cells in an animal c...
Background:
Human immunodeficiency virus (HIV)-infected persons are at higher risk for serious complications associated with traditional smallpox vaccines. Alternative smallpox vaccines with an improved safety profile would address this unmet medical need.
Methods:
The safety and immunogenicity of modified vaccinia Ankara (MVA) was assessed in 9...
Sustained activation of the Raf/MEK/extracellular signal-regulated kinase (ERK) pathway in infected cells has been shown to be crucial for full replication efficiency of orthopoxviruses in cell culture. In infected cells, this pathway is mainly activated by the vaccinia virus growth factor (VGF), an epidermal growth factor (EGF)-like protein. We sh...
Dendritic cells (DCs) can be segregated into various subsets based on phenotypic and functional differences. Whereas plasmacytoid DCs are known for their type I interferon (IFN) producing capacity, conventional (c) DCs are better known for their roles in T cell homeostasis and priming. Among cDCs the CD8α+ subset is especially efficient in producin...
Polyinosinic:polycytidylic acid (poly IC), a double-stranded RNA, is an effective adjuvant in vivo. IFN-λs (also termed IL-28/29) are potent immunomodulatory and antiviral cytokines. We demonstrate that poly IC injection in vivo induces large amounts of IFN-λ, which depended on hematopoietic cells and the presence of TLR3 (Toll-like receptor 3), IR...
Modified vaccinia virus Ankara (MVA) has a highly restricted host range in cell culture and is apathogenic in vivo. MVA was derived from the parental chorioallantois vaccinia virus Ankara (CVA) by more than 570 passages in chicken embryo fibroblast (CEF) cells. During CEF cell passaging, six major deletions comprising 24,668 nucleotides occurred in...
The findings of Martinez et al. (1) that vaccinia virus and its DNA are potent inducers of plasmacytoid dendritic cell (pDC)-derived IFN-α in a Toll-like receptor (TLR)9-independent, exclusively TLR8-dependent way came to us as a great surprise (2). The data (1) contradict our results and those of others.
Efficient T-cell responses against recombinant antigens expressed by vaccinia virus vectors require expression of these antigens in the early phase of the virus replication cycle. The kinetics of recombinant gene expression in poxviruses are largely determined by the promoter chosen. We used the highly attenuated modified vaccinia virus Ankara (MVA...
Current prophylactic vaccines work via the induction of B and T cell mediated memory that effectively control further replication of the pathogen after entry. In the case of therapeutic or post-exposure vaccinations the situation is far more complex, because the pathogen has time to establish itself in the host, start producing immune-inhibitory mo...
IMVAMUNE is a Modified Vaccinia Ankara (MVA)-based virus that is being developed as a safer 3rd generation smallpox vaccine. In order to determine the optimal dose for further development, a double-blind, randomized Phase II trial was performed testing three different doses of IMVAMUNE in 164 healthy volunteers. All three IMVAMUNE doses displayed a...
Infection of rabbits with aerosolized rabbitpox virus (RPXV) produces a disease similar to monkeypox and smallpox in humans and provides a valuable, informative model system to test medical countermeasures against orthopoxviruses. Due to the eradication of smallpox, the evaluation of the efficacy of new-generation smallpox vaccines depends on relev...
Modified vaccinia Ankara (MVA) was developed by serial passages on chicken embryo fibroblast cells. After passage 570, the virus was considered homogenous and genetically stable. Three MVA strains (MVA-572, MVA-I721 and MVA-BN) have been analyzed and shown to be 100% genetically identical; although significant differences in their phenotypes were i...
Background: Classical, replication competent smallpox vaccines (e.g., Dryvax®) have the potential to cause serious complications, especially in immunocompromised individuals. Prior to 1974 Modified Vaccinia Ankara (MVA) was safely administered as a pre-vaccine to 120,000 people in Germany. MVA lost ~15% of its parent genome and (a) was non-replicat...
Poxviruses such as the causative agent of smallpox have developed multiple strategies to suppress immune responses, including the suppression of DC activation. Since poxviruses are large DNA viruses, we hypothesized that their detection by DCs may involve the endosomal DNA recognition receptor TLR9. Indeed, we have shown here that DC recognition of...
Smallpox vaccination with replication deficient vaccinia strains such as Modified Vaccinia Ankara (MVA) may induce protective immunity with improved safety and tolerability profiles compared with currently available smallpox vaccines. Ninety subjects were randomized equally to six groups in a partially blinded, randomized, controlled clinical trial...