Whitney Weber

All Publications

• Development of a virulent O'nyong'nyong challenge model to determine heterologous protection mediated by a hydrogen peroxide-inactivated chikungunya virus vaccine. PLoS neglected tropical diseases Weber, W. C., Streblow, Z. J., Andoh, T. F., Denton, M., Raué, H. P., Amanna, I. J., Slifka, D. K., Kreklywich, C. N., Arduino, I., Sulgey, G., Streblow, M. M., Heise, M. T., Slifka, M. K., Streblow, D. N. 2025; 19 (3): e0012938

  Abstract

  O'nyong-nyong virus (ONNV) is a mosquito-transmitted alphavirus identified in Uganda in 1959. The virus has potential for enzootic and urban transmission cycles, and in humans, ONNV infection manifests as fever, rash, and joint/muscle pain that can persist. There are currently no specific vaccines or antiviral treatments for ONNV. Since highly passaged alphaviruses often lose pathogenic features, we constructed an infectious clone for ONNV-UVRI0804 (ONNV0804), a 2017 isolate from a febrile patient in Uganda. Viral replication for ONNV0804 was compared to the highly passaged strain, ONNVUgMP30, and ONNVUgMP30 replicated to higher levels in human dermal fibroblasts and Vero cells, but both viruses replicated similarly in C6/36 and mouse embryonic fibroblast cells. We performed a head-to-head comparison of in vivo virulence in both immunocompetent C57BL/6 mice and interferon deficient AG129 mice. In both mouse strains, ONNV0804 was substantially more pathogenic than ONNVUgMP30. Unlike ONNVUgMP30, ONNV0804 caused significant footpad swelling and broader tissue distribution with higher vRNA loads at both 5- and 43-days post-infection (dpi) relative to ONNVUgMP30. This finding indicates that ONNV can persist in joint and muscle tissues for long periods of time, which has been associated with chronic arthritogenic human disease. In AG129 mice, ONNV0804 caused a more rapid onset of disease, higher viremia, and a >800-fold increase in virulence. Previous studies have shown that CHIKV infection or vaccination can provide cross-reactive immunity to ONNV. To determine if a CHIKV vaccine can protect against the more virulent ONNV0804 strain, we vaccinated mice with a hydrogen peroxide-inactivated CHIKV vaccine, HydroVax-CHIKV. Neutralizing antibody titers were determined against ONNV0804 and CHIKV and animals were challenged with ONNV0804. An optimized two-dose vaccination regimen of HydroVax-CHIKV protected against lethal infection and reduced virus-associated arthritogenic disease. These data indicate that we have developed new and robust models for studying severe ONNV disease and that HydroVax-CHIKV vaccination can protect against infection with a highly pathogenic contemporary strain of ONNV.

  View details for DOI 10.1371/journal.pntd.0012938

  View details for PubMedID 40096126

• Chikungunya Virus Vaccines: A Review of IXCHIQ and PXVX0317 from Pre-Clinical Evaluation to Licensure BIODRUGS Weber, W. C., Streblow, D. N., Coffey, L. L. 2024; 38 (6): 727-742

  Abstract

  Chikungunya virus is an emerging mosquito-borne alphavirus that causes febrile illness and arthritic disease. Chikungunya virus is endemic in 110 countries and the World Health Organization estimates that it has caused more than 2 million cases of crippling acute and chronic arthritis globally since it re-emerged in 2005. Chikungunya virus outbreaks have occurred in Africa, Asia, Indian Ocean islands, South Pacific islands, Europe, and the Americas. Until recently, no specific countermeasures to prevent or treat chikungunya disease were available. To address this need, multiple vaccines are in human trials. These vaccines use messenger RNA-lipid nanoparticles, inactivated virus, and viral vector approaches, with a live-attenuated vaccine VLA1553 and a virus-like particle PXVX0317 in phase III testing. In November 2023, the US Food and Drug Administration (FDA) approved the VLA1553 live-attenuated vaccine, which is marketed as IXCHIQ. In June 2024, Health Canada approved IXCHIQ, and in July 2024, IXCHIQ was approved by the European Commission. On August 13, 2024, the US FDA granted priority review for PXVX0317. The European Medicine Agency is considering accelerated assessment review of PXVX0317, with potential for approval by both agencies in 2025. In this review, we summarize published data from pre-clinical and clinical trials for the IXCHIQ and PXVX0317 vaccines. We also discuss unanswered questions including potential impacts of pre-existing chikungunya virus immunity on vaccine safety and immunogenicity, whether long-term immunity can be achieved, safety in children, pregnant, and immunocompromised individuals, and vaccine efficacy in people with previous exposure to other emerging alphaviruses in addition to chikungunya virus.

  View details for DOI 10.1007/s40259-024-00677-y

  View details for Web of Science ID 001315574900001

  View details for PubMedID 39292392

  View details for PubMedCentralID PMC11530495

• Nonreciprocity in CHIKV and MAYV Vaccine-Elicited Protection. Vaccines Weber, W. C., Andoh, T. F., Kreklywich, C. N., Streblow, Z. J., Denton, M., Streblow, M. M., Powers, J. M., Sulgey, G., Medica, S., Dmitriev, I., Curiel, D. T., Haese, N. N., Streblow, D. N. 2024; 12 (9)

  Abstract

  Chikungunya virus (CHIKV) is a pathogenic arthritogenic alphavirus responsible for large-scale human epidemics for which a vaccine was recently approved for use. Mayaro virus (MAYV) is a related emerging alphavirus with epidemic potential with circulation overlap potential with CHIKV. We previously reported the ability of a non-replicating human adenovirus (AdV)-vectored vaccine expressing the MAYV structural polyprotein to protect against disease in mice following challenge with MAYV, CHIKV and UNAV. Herein, we evaluated mouse immunity and protective efficacy for an AdV-CHIKV full structural polyprotein vaccine in combination with heterologous AdV-MAYV prime/boost regimens versus vaccine coadministration. Heterologous prime/boost regimens skewed immunity toward the prime vaccine antigen but allowed for a boost of cross-neutralizing antibodies, while vaccine co-administration elicited robust, balanced responses capable of boosting. All immunization strategies protected against disease from homologous virus infection, but reciprocal protective immunity differences were revealed upon challenge with heterologous viruses. In vivo passive transfer experiments reproduced the inequity in reciprocal cross-protection after heterologous MAYV challenge. We detected in vitro antibody-dependent enhancement of MAYV replication, suggesting a potential mechanism for the lack of cross-protection. Our findings provide important insights into rational alphavirus vaccine design that may have important implications for the evolving alphavirus vaccine landscape.

  View details for DOI 10.3390/vaccines12090970

  View details for PubMedID 39340002

  View details for PubMedCentralID PMC11435824

• The Approved Live-Attenuated Chikungunya Virus Vaccine (IXCHIQ®) Elicits Cross-Neutralizing Antibody Breadth Extending to Multiple Arthritogenic Alphaviruses Similar to the Antibody Breadth Following Natural Infection VACCINES Weber, W. C., Streblow, Z. J., Kreklywich, C. N., Denton, M., Sulgey, G., Streblow, M. M., Marcano, D., Flores, P. N., Rodriguez-Santiago, R. M., Alvarado, L. I., Rivera-Amill, V., Messer, W. B., Hochreiter, R., Kosulin, K., Dubischar, K., Buerger, V., Streblow, D. N. 2024; 12 (8)

  Abstract

  The first vaccine against chikungunya virus (CHIKV) was recently licensed in the U.S., Europe, and Canada (brand IXCHIQ®, referred to as VLA1553). Other pathogenic alphaviruses co-circulate with CHIKV and major questions remain regarding the potential of IXCHIQ to confer cross-protection for populations that are exposed to them. Here, we characterized the cross-neutralizing antibody (nAb) responses against heterotypic CHIKV and additional arthritogenic alphaviruses in individuals at one month, six months, and one year post-IXCHIQ vaccination. We characterized nAbs against CHIKV strains LR2006, 181/25, and a 2021 isolate from Tocantins, Brazil, as well as O'nyong-nyong virus (ONNV), Mayaro virus (MAYV), and Ross River virus (RRV). IXCHIQ elicited 100% seroconversion to each virus, with the exception of RRV at 83.3% seroconversion of vaccinees, and cross-neutralizing antibody potency decreased with increasing genetic distance from CHIKV. We compared vaccinee responses to cross-nAbs elicited by natural CHIKV infection in individuals living in the endemic setting of Puerto Rico at 8-9 years post-infection. These data suggest that IXCHIQ efficiently and potently elicits cross-nAb breadth that extends to related alphaviruses in a manner similar to natural CHIKV infection, which may have important implications for individuals that are susceptible to alphavirus co-circulation in regions of potential vaccine rollout.

  View details for DOI 10.3390/vaccines12080893

  View details for Web of Science ID 001306687700001

  View details for PubMedID 39204019

  View details for PubMedCentralID PMC11359099

• Mayaro virus pathogenesis and immunity in rhesus macaques. PLoS neglected tropical diseases Weber, W. C., Labriola, C. S., Kreklywich, C. N., Ray, K., Haese, N. N., Andoh, T. F., Denton, M., Medica, S., Streblow, M. M., Smith, P. P., Mizuno, N., Frias, N., Fisher, M. B., Barber-Axthelm, A. M., Chun, K., Uttke, S., Whitcomb, D., DeFilippis, V., Rakshe, S., Fei, S. S., Axthelm, M. K., Smedley, J. V., Streblow, D. N. 2023; 17 (11): e0011742

  Abstract

  Mayaro virus (MAYV) is a mosquito-transmitted alphavirus that causes debilitating and persistent arthritogenic disease. While MAYV was previously reported to infect non-human primates (NHP), characterization of MAYV pathogenesis is currently lacking. Therefore, in this study we characterized MAYV infection and immunity in rhesus macaques. To inform the selection of a viral strain for NHP experiments, we evaluated five MAYV strains in C57BL/6 mice and showed that MAYV strain BeAr505411 induced robust tissue dissemination and disease. Three male rhesus macaques were subcutaneously challenged with 105 plaque-forming units of this strain into the arms. Peak plasma viremia occurred at 2 days post-infection (dpi). NHPs were taken to necropsy at 10 dpi to assess viral dissemination, which included the muscles and joints, lymphoid tissues, major organs, male reproductive tissues, as well as peripheral and central nervous system tissues. Histological examination demonstrated that MAYV infection was associated with appendicular joint and muscle inflammation as well as presence of perivascular inflammation in a wide variety of tissues. One animal developed a maculopapular rash and two NHP had viral RNA detected in upper torso skin samples, which was associated with the presence of perivascular and perifollicular lymphocytic aggregation. Analysis of longitudinal peripheral blood samples indicated a robust innate and adaptive immune activation, including the presence of anti-MAYV neutralizing antibodies with activity against related Una virus and chikungunya virus. Inflammatory cytokines and monocyte activation also peaked coincident with viremia, which was well supported by our transcriptomic analysis highlighting enrichment of interferon signaling and other antiviral processes at 2 days post MAYV infection. The rhesus macaque model of MAYV infection recapitulates many of the aspects of human infection and is poised to facilitate the evaluation of novel therapies and vaccines targeting this re-emerging virus.

  View details for DOI 10.1371/journal.pntd.0011742

  View details for PubMedID 37983245

  View details for PubMedCentralID PMC10695392

• Infection with chikungunya virus confers heterotypic cross-neutralizing antibodies and memory B-cells against other arthritogenic alphaviruses predominantly through the B domain of the E2 glycoprotein. PLoS neglected tropical diseases Powers, J. M., Lyski, Z. L., Weber, W. C., Denton, M., Streblow, M. M., Mayo, A. T., Haese, N. N., Nix, C. D., Rodríguez-Santiago, R., Alvarado, L. I., Rivera-Amill, V., Messer, W. B., Streblow, D. N. 2023; 17 (3): e0011154

  Abstract

  Infections with Chikungunya virus, a mosquito-borne alphavirus, cause an acute febrile syndrome often followed by chronic arthritis that persists for months to years post-infection. Neutralizing antibodies are the primary immune correlate of protection elicited by infection, and the major goal of vaccinations in development. Using convalescent blood samples collected from both endemic and non-endemic human subjects at multiple timepoints following suspected or confirmed chikungunya infection, we identified antibodies with broad neutralizing properties against other alphaviruses within the Semliki Forest complex. Cross-neutralization generally did not extend to the Venezuelan Equine Encephalitis virus (VEEV) complex, although some subjects had low levels of VEEV-neutralizing antibodies. This suggests that broadly neutralizing antibodies elicited following natural infection are largely complex restricted. In addition to serology, we also performed memory B-cell analysis, finding chikungunya-specific memory B-cells in all subjects in this study as remotely as 24 years post-infection. We functionally assessed the ability of memory B-cell derived antibodies to bind to chikungunya virus, and related Mayaro virus, as well as the highly conserved B domain of the E2 glycoprotein thought to contribute to cross-reactivity between related Old-World alphaviruses. To specifically assess the role of the E2 B domain in cross-neutralization, we depleted Mayaro and Chikungunya virus E2 B domain specific antibodies from convalescent sera, finding E2B depletion significantly decreases Mayaro virus specific cross-neutralizing antibody titers with no significant effect on chikungunya virus neutralization, indicating that the E2 B domain is a key target of cross-neutralizing and potentially cross-protective neutralizing antibodies.

  View details for DOI 10.1371/journal.pntd.0011154

  View details for PubMedID 36913428

  View details for PubMedCentralID PMC10036167

• Development of a next-generation chikungunya virus vaccine based on the HydroVax platform. PLoS pathogens Slifka, D. K., Raué, H. P., Weber, W. C., Andoh, T. F., Kreklywich, C. N., DeFilippis, V. R., Streblow, D. N., Slifka, M. K., Amanna, I. J. 2022; 18 (7): e1010695

  Abstract

  Chikungunya virus (CHIKV) is an emerging/re-emerging mosquito-borne pathogen responsible for explosive epidemics of febrile illness characterized by debilitating polyarthralgia and the risk of lethal infection among the most severe cases. Despite the public health risk posed by CHIKV, no vaccine is currently available. Using a site-directed hydrogen peroxide-based inactivation approach, we developed a new CHIKV vaccine, HydroVax-CHIKV. This vaccine technology was compared to other common virus inactivation approaches including β-propiolactone (BPL), formaldehyde, heat, and ultraviolet (UV) irradiation. Heat, UV, and BPL were efficient at inactivating CHIKV-181/25 but caused substantial damage to neutralizing epitopes and failed to induce high-titer neutralizing antibodies in vaccinated mice. HydroVax-CHIKV and formaldehyde-inactivated CHIKV retained intact neutralizing epitopes similar to live virus controls but the HydroVax-CHIKV approach demonstrated a more rapid rate of virus inactivation. HydroVax-CHIKV vaccination induced high neutralizing responses to homologous and heterologous CHIKV clades as well as to other alphaviruses including Mayaro virus, O'nyong'nyong virus, and Una virus. Following heterologous infection with CHIKV-SL15649, HydroVax-CHIKV-immunized mice were protected against viremia, CHIKV-associated arthritic disease, and lethal CHIKV infection by an antibody-dependent mechanism. In contrast, animals vaccinated with Heat- or UV-inactivated virus showed no protection against viremia in addition to demonstrating significantly exacerbated CD4+ T cell-mediated footpad swelling after CHIKV infection. Together, these results demonstrate the risks associated with using suboptimal inactivation methods that fail to elicit protective neutralizing antibody responses and show that HydroVax-CHIKV represents a promising new vaccine candidate for prevention of CHIKV-associated disease.

  View details for DOI 10.1371/journal.ppat.1010695

  View details for PubMedID 35788221

  View details for PubMedCentralID PMC9286250