Center for Immunization Research

North Bethesda, MD, United States

Center for Immunization Research

North Bethesda, MD, United States
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Robinson M.L.,Center for Immunization Research
Current Opinion in Infectious Diseases | Year: 2017

PURPOSE OF REVIEW: Dengue, the most common arbovirus, is an increasingly significant cause of morbidity worldwide. After decades of research, an approved tetravalent dengue vaccine is finally available. Models constructed using recently available vaccine efficacy data allow for a data-driven discussion of the potential impact of dengue vaccine deployment on global control. RECENT FINDINGS: Phase 3 efficacy trials demonstrated that the approved dengue vaccine, chimeric yellow fever–dengue–tetravalent dengue vaccine, has an efficacy of 60% against dengue illness of any severity. However, among dengue unexposed recipients, vaccination offers limited efficacy and may increase dengue severity. The WHO consequently recommends dengue vaccination for populations in which 70% of intended recipients are dengue seropositive. Models predict that routine childhood dengue vaccine may reduce dengue burden, but over time, population-level impact may be limited. Additional vaccine candidates in late-stage development may not suffer from the same limitations as chimeric yellow fever–dengue–tetravalent dengue vaccine. SUMMARY: The efficacy and safety profile of the recently approved dengue vaccine is favorable only in previously dengue exposed recipients, which limits its potential for global control. Future work must evaluate the approved vaccineʼs long-term durability, efficacy of other late phase vaccine candidates, and potential for vector control efforts to work synergistically with vaccine deployment. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.


Lindow J.C.,University of Vermont | Durbin A.P.,Center for Immunization Research | Whitehead S.S.,National Institute of Allergy and Infectious Diseases | Pierce K.K.,University of Vermont | And 2 more authors.
Vaccine | Year: 2013

There are currently no vaccines or therapeutics to prevent dengue disease which ranges in severity from asymptomatic infections to life-threatening illness. The National Institute of Allergy and Infectious Diseases (NIAID) Division of Intramural Research has developed live, attenuated vaccines to each of the four dengue serotypes (DENV-1-DENV-4). Two doses (10. PFU and 1000. PFU) of three monovalent vaccines were tested in human clinical trials to compare safety and immunogenicity profiles. DEN4δ30 had been tested previously at multiple doses. The three dengue vaccine candidates tested (DEN1δ30, DEN2/4δ30, and DEN3δ30/31) were very infectious, each with a human infectious dose 50%. ≤. 10. PFU. Further, infectivity rates ranged from 90 to 100% regardless of dose, excepting DEN2/4δ30 which dropped from 100% at the 1000. PFU dose to 60% at the 10. PFU dose. Mean geometric peak antibody titers did not differ significantly between doses for DEN1δ30 (92 ± 19 vs. 214 ± 97, p=. 0.08); however, significant differences were observed between the 10. PFU and 1000. PFU doses for DEN2/4δ30, 19 ± 9 vs. 102 ± 25 (p=. 0.001), and DEN3δ30/31, 119 ± 135 vs. 50 ± 50 (p=. 0.046). No differences in the incidences of rash, neutropenia, or viremia were observed between doses for any vaccines, though the mean peak titer of viremia for DEN1δ30 was higher at the 1000. PFU dose (0.5 ± 0 vs. 1.1 ± 0.1, p=. 0.007). These data demonstrate that a target dose of 1000. PFU for inclusion of each dengue serotype into a tetravalent vaccine is likely to be safe and generate a balanced immune response for all serotypes. © 2013 Elsevier Ltd.


Karron R.A.,Center for Immunization Research | Luongo C.,National Institute of Allergy and Infectious Diseases | Thumar B.,Center for Immunization Research | Loehr K.M.,Center for Immunization Research | And 3 more authors.
Science Translational Medicine | Year: 2015

Respiratory syncytial virus (RSV) is the leading viral cause of severe pediatric respiratory illness, and a safe and effective vaccine for use in infancy and early childhood is needed. We previously showed that deletion of the coding sequence for the viral M2-2 protein (DM2-2) down-regulated viral RNA replication and up-regulated gene transcription and antigen synthesis, raising the possibility of development of an attenuated vaccine with enhanced immunogenicity. RSV MEDI DM2-2 was therefore evaluated as a live intranasal vaccine in adults, RSV-seropositive children, and RSV-seronegative children. When results in RSV-seronegative children were compared to those achieved with the previous leading live attenuated RSV candidate vaccine, vaccine virus shedding was significantly more restricted, yet the postvaccination RSV-neutralizing serum antibody achieved [geometric mean titer (GMT) = 1:97] was significantly greater. Surveillance during the subsequent RSV season showed that several seronegative RSV MEDI DM2-2 recipients had substantial antibody rises without reported illness, suggesting that the vaccine was protective yet primed for anamnestic responses to RSV. Rational design appears to have yielded a candidate RSV vaccine that is intrinsically superior at eliciting protective antibody in RSV-naïve children and highlights an approach for the development of live attenuated RSV vaccines.


Durbin A.P.,Center for Immunization Research | Kirkpatrick B.D.,University of Vermont | Pierce K.K.,University of Vermont | Schmidt A.C.,National Institute of Allergy and Infectious Diseases | Whitehead S.S.,National Institute of Allergy and Infectious Diseases
Vaccine | Year: 2011

The Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health has been engaged in an effort to develop a safe, efficacious, and affordable live attenuated tetravalent dengue vaccine (LATV) for more than ten years. Numerous recombinant monovalent DENV vaccine candidates have been evaluated in the SCID-HuH-7 mouse and in rhesus macaques to identify those candidates with a suitable attenuation phenotype. In addition, the ability of these candidates to infect and disseminate in Aedes mosquitoes had also been determined. Those candidates that were suitably attenuated in SCID-HuH-7 mice, rhesus macaques, and mosquitoes were selected for further evaluation in humans. This review will describe the generation of multiple candidate vaccines directed against each DENV serotype, the preclinical and clinical evaluation of these candidates, and the process of selecting suitable candidates for inclusion in a LATV dengue vaccine. © 2011 Elsevier Ltd.


Durbin A.P.,Center for Immunization Research | Whitehead S.S.,National Institute of Allergy and Infectious Diseases
Viruses | Year: 2011

Dengue has become the most important arboviral infection worldwide with more than 30 million cases of dengue fever estimated to occur each year. The need for a dengue vaccine is great and several live attenuated dengue candidate vaccines are proceeding through clinical evaluation. The need to induce a balanced immune response against all four DENV serotypes with a single vaccine has been a challenge for dengue vaccine developers. A live attenuated DENV chimeric vaccine produced by Sanofi Pasteur has recently entered Phase III evaluation in numerous dengue-endemic regions of the world. Viral interference between serotypes contained in live vaccines has required up to three doses of the vaccine be given over a 12-month period of time. For this reason, novel DENV candidate vaccines are being developed with the goal of achieving a protective immune response with an immunization schedule that can be given over the course of a few months. These next-generation candidates include DNA vaccines, recombinant adenovirus vectored vaccines, alphavirus replicons, and sub-unit protein vaccines. Several of these novel candidates will be discussed. © 2011 by the authors; licensee MDPI, Basel, Switzerland.


Karron R.A.,Center for Immunization Research | Thumar B.,Center for Immunization Research | Schappell E.,Center for Immunization Research | Surman S.,National Institute of Allergy and Infectious Diseases | And 3 more authors.
Vaccine | Year: 2012

Human parainfluenza virus type 3 (HPIV3) is an important cause of lower respiratory tract illness in children, yet a licensed vaccine or antiviral drug is not available. We evaluated the safety, tolerability, infectivity, and immunogenicity of two intranasal, live-attenuated HPIV3 vaccines, designated rHPIV3-N B and rB/HPIV3, that were cDNA-derived chimeras of HPIV3 and bovine PIV3 (BPIV3). These were evaluated in adults, HPIV3 seropositive children, and HPIV3 seronegative children. A total of 112 subjects participated in these studies. Both rB/HPIV3 and rHPIV3-N B were highly restricted in replication in adults and seropositive children but readily infected seronegative children, who shed mean peak virus titers of 10 2.8 vs. 10 3.7pfu/mL, respectively. Although rB/HPIV3 was more restricted in replication in seronegative children than rHPIV3-N B, it induced significantly higher titers of hemagglutination inhibition (HAI) antibodies against HPIV3. Taken together, these data suggest that the rB/HPIV3 vaccine is the preferred candidate for further clinical development. © 2012.


Durbin A.P.,Center for Immunization Research
Seminars in Reproductive Medicine | Year: 2016

Zika virus is a mosquito-borne Flavivirus that spread rapidly through South and Central America in 2015 to 2016. Microcephaly has been causally associated with Zika virus infection during pregnancy and the World Health Organization declared Zika virus as a Public Health Emergency of International Concern. To address this crisis, many groups have expressed their commitment to developing a Zika virus vaccine. Different strategies for Zika virus vaccine development are being considered including recombinant live attenuated vaccines, purified inactivated vaccines (PIVs), DNA vaccines, and viral vectored vaccines. Important to Zika virus vaccine development will be the target group chosen for vaccination and which end point(s) is chosen for efficacy determination. The first clinical trials of Zika virus vaccine candidates will begin in Q3/4 2016 but the pathway to licensure for a Zika virus vaccine is expected to take several years. Efforts are ongoing to accelerate Zika virus vaccine development and evaluation with the ultimate goal of reducing time to licensure. Copyright ©, Thieme Medical Publishers. All rights reserved.


Dowd K.A.,U.S. National Institutes of Health | Jost C.A.,U.S. National Institutes of Health | Durbin A.P.,Center for Immunization Research | Whitehead S.S.,U.S. National Institutes of Health | Pierson T.C.,U.S. National Institutes of Health
PLoS Pathogens | Year: 2011

Neutralizing antibodies are a significant component of the host's protective response against flavivirus infection. Neutralization of flaviviruses occurs when individual virions are engaged by antibodies with a stoichiometry that exceeds a required threshold. From this "multiple-hit" perspective, the neutralizing activity of antibodies is governed by the affinity with which it binds its epitope and the number of times this determinant is displayed on the surface of the virion. In this study, we investigated time-dependent changes in the fate of West Nile virus (WNV) decorated with antibody in solution. Experiments with the well-characterized neutralizing monoclonal antibody (MAb) E16 revealed a significant increase in neutralization activity over time that could not be explained by the kinetics of antibody binding, virion aggregation, or the action of complement. Additional kinetic experiments using the fusion-loop specific MAb E53, which has limited neutralizing activity because it recognizes a relatively inaccessible epitope on mature virions, identified a role of virus "breathing" in regulating neutralization activity. Remarkably, MAb E53 neutralized mature WNV in a time- and temperature-dependent manner. This phenomenon was confirmed in studies with a large panel of MAbs specific for epitopes in each domain of the WNV envelope protein, with sera from recipients of a live attenuated WNV vaccine, and in experiments with dengue virus. Given enough time, significant inhibition of infection was observed even for antibodies with very limited, or no neutralizing activity in standard neutralization assays. Together, our data suggests that the structural dynamics of flaviviruses impacts antibody-mediated neutralization via exposure of otherwise inaccessible epitopes, allowing for antibodies to dock on the virion with a stoichiometry sufficient for neutralization.


Mukherjee S.,U.S. National Institutes of Health | Dowd K.A.,U.S. National Institutes of Health | Manhart C.J.,U.S. National Institutes of Health | Ledgerwood J.E.,U.S. National Institutes of Health | And 3 more authors.
Journal of Virology | Year: 2014

The production of neutralizing antibodies (NAbs) is a correlate of protection for many human vaccines, including currently licensed vaccines against flaviviruses. NAbs are typically measured using a plaque reduction neutralization test (PRNT). Despite its extensive use, parameters that impact the performance of the PRNT have not been investigated from a mechanistic perspective. The results of a recent phase IIb clinical trial of a tetravalent dengue virus (DENV) vaccine suggest that NAbs, as measured using a PRNT performed with Vero cells, do not correlate with protection. This surprising finding highlights the importance of understanding how well the PRNT captures the complexity of the NAb response to DENV. In this study, we demonstrated that the structural heterogeneity of flaviviruses arising from inefficient virion maturation impacts the results of neutralization assays in a cell type-dependent manner. Neutralization titers of several monoclonal antibodies were significantly reduced when assayed on Vero cells compared to Raji cells expressing DC-SIGNR. This pattern can be explained by differences in the efficiency with which partially mature flaviviruses attach to each cell type, rather than a differential capacity of antibody to block infection. Vero cells are poorly permissive to the fraction of virions that are most sensitive to neutralization. Analysis of sera from recipients of live-attenuated monovalent DENV vaccine candidates revealed a strong correlation between the sensitivity of serum antibodies to the maturation state of DENV and cell type-dependent patterns of neutralization. Cross-reactive patterns of neutralization may be underrepresented by the "gold-standard" PRNT that employs Vero cells. © 2014, American Society for Microbiology.


Kirkpatrick B.D.,University of Vermont | Whitehead S.S.,National Institutes of Allergy and Infectious Diseases | Pierce K.K.,University of Vermont | Tibery C.M.,Center for Immunization Research | And 10 more authors.
Science Translational Medicine | Year: 2016

A dengue human challenge model can be an important tool to identify candidate dengue vaccines that should be further evaluated in large efficacy trials in endemic areas. Dengue is responsible for about 390 million infections annually. Protective efficacy results for the most advanced dengue vaccine candidate (CYD) were disappointing despite its ability to induce neutralizing antibodies against all four dengue virus (DENV) serotypes. TV003 is a live attenuated tetravalent DENV vaccine currently in phase 2 evaluation. To better assess the protective efficacy of TV003, a randomized double-blind, placebo-controlled trial in which recipients of TV003 or placebo were challenged 6 months later with a DENV-2 strain, rDEN2D30, was conducted. The primary endpoint of the trial was protection against dengue infection, defined as rDEN2D30 viremia. Secondary endpoints were protection against rash and neutropenia. All 21 recipients of TV003 who were challenged with rDEN2D30 were protected from infection with rDEN2D30. None developed viremia, rash, or neutropenia after challenge. In contrast, 100% of the 20 placebo recipients who were challenged with rDEN2D30 developed viremia, 80% developed rash, and 20% developed neutropenia. TV003 induced complete protection against challenge with rDEN2D30 administered 6months after vaccination. TV003 will be further evaluated in dengue-endemic areas. The controlled dengue human challenge model can accelerate vaccine development by evaluating the protection afforded by the vaccine, thereby eliminating poor candidates from further consideration before the initiation of large efficacy trials.

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