Biology subjects

Hirsch, A. J.

Publications and source records attributed to Hirsch, A. J..

4 recordsLinked to original sources

bioRxiv2025

A Zika Virus-Like Particle Vaccine Mitigates Early Pregnancy Loss In Rhesus Macaques

Zika virus (ZIKV) is an arthropod-borne Orthoflavivirus that caused a major outbreak in the Americas in 2015-16. In Brazil, up to 46% of ZIKV positive pregnancies resulted in congenital Zika syndrome (CZS). CZS is characterized by a wide range of neurologic birth defects and miscarriage in up to 7.6% of affected pregnancies. With no current licensed ZIKV vaccines, we sought to evaluate a Zika virus-like particle (VLP) vaccine candidate in a rhesus macaque (RM) pregnancy model. VLPs were produced in mammalian cells expressing the pre-membrane-envelope region of the Asian-lineage ZIKV strain PRVABC59, which belongs to the Asian ZIKV lineage that is associated with outbreaks of congenital disease. To evaluate vaccine protection against adverse pregnancy complications, two cohorts of female RM were vaccinated with ZIKV-VLP with adjuvant Alhydrogel (alum) or adjuvant alone prior to mating. At gestational day (GD) 30 (early first trimester), pregnant animals were challenged with ZIKV-DAK 41524, an African-lineage strain shown to induce 1st-trimester fetal demise in 78% (n=11/14 animals) of RM, making it an ideal and stringent model for evaluating ZIKV vaccines. Within the vaccinated cohort, 2 of 3 animals reached the study endpoint of GD 90 with no observed adverse pregnancy outcomes. The third animal experienced pregnancy loss at GD 49 (18 d post infection), although no infectious virus was detected in placental or fetal tissues. In the unvaccinated cohort, two animals had severe adverse events. One animal experienced preterm labor, and another developed early-onset hydrops fetalis with widespread ZIKV-RNA detected via RNAscope and extensive placental damage. These results confirm a significant risk for early pregnancy loss in RM infected with ZIKV-DAK 41524. This model can be further used to understand the complexities of placental immunological features underlying stillbirth and miscarriage following infection. Our findings indicate that this ZIKV-VLP vaccine candidate protected pregnant macaques against fetal demise associated with highly pathogenic ZIKV challenge. Author SummaryZika virus (ZIKV) infection during pregnancy is associated with pregnancy loss, severe birth defects, including microcephaly and developmental delays, and other subtle neurologic changes. Although vaccine development efforts have been ongoing since the 2015/2016 ZIKV outbreak, no approved vaccine is currently available. Many existing studies have tested vaccines in animal models using strains such as ZIKV-PR that cause mild or moderate pregnancy complications at similar rates to human cases. Using challenge strains that only cause mild, or moderate pregnancy complications makes it difficult to rigorously evaluate vaccine efficacy. In this study, we tested a virus-like particle (VLP) vaccine, a safe and effective method for use during pregnancy as it is replication-deficient and only contains viral structural antigens. We found that the VLP vaccine, when paired with an adjuvant (alum), induced strong antibody responses in mice and controlled viral dissemination following challenge in nonpregnant macaques. To evaluate the protective efficacy of the ZIKV-VLP vaccine against in utero infection and disease, we used a stringent model of ZIKV infection during early pregnancy in rhesus macaques that is associated with high rates of fetal demise. In pregnant macaques, the vaccine reduced maternal viremia, limited viral spread to fetal and placental tissues, and conferred protection against virus-mediated fetal demise and placental damage. This is the first study to evaluate a VLP-based vaccine in a consistent pregnancy loss model of ZIKV infection. These findings support the continued development of VLP vaccines as a safe and effective strategy for protecting pregnant individuals and their developing fetuses from ZIKV.

microbiology↗

bioRxiv2025

Effect of obesity on the acute response to SARS-CoV-2 infection and development of post-acute sequelae of COVID-19 (PASC) in nonhuman primates

Long-term adverse consequences of SARS-CoV-2 infection, termed "long COVID" or post-acute sequelae of COVID (PASC), are a major component of overall COVID-19 disease burden. Prior obesity and metabolic disease increase the severity of acute disease, but SARS-CoV-2 infection also contributes to the development of new-onset metabolic disease. Since the COVID pandemic occurred in the context of the global obesity epidemic, an important question is the extent to which pre-existing obesity modifies long-term responses to SARS-CoV-2 infection. We utilized a nonhuman primate model to compare the effects of infection with the SARS-CoV-2 delta variant in lean and obese/insulin-resistant adult male rhesus macaques over a 6-month time course. While some longitudinal responses to SARS-CoV-2 infection, including overall viral dynamics, SARS-CoV-2-specific IgG induction, cytokine profiles, and tissue persistence of viral RNA, did not appreciably differ between lean and obese animals, other responses, including neutralizing Ab dynamics, lung pathology, body weight, degree of insulin sensitivity, adipocytokine profiles, body temperature, and nighttime activity levels were significantly different in lean versus obese animals. Furthermore, several parameters in lean animals were altered following SARS-CoV-2 infection to resemble those in obese animals. Notably, persistent changes in multiple parameters were present in most animals, suggesting that PASC may be more prevalent than estimated from self-reported symptoms in human studies.

pathology↗

bioRxiv2024

The TLR7/8 agonist INI-4001 enhances the immunogenicity of a Powassan virus-like-particle vaccine

Powassan virus (POWV) is a pathogenic tick-borne flavivirus that causes fatal neuroinvasive disease in humans. There are currently no approved therapies or vaccines for POWV infection. Here, we develop a POW virus-like-particle (POW-VLP) based vaccine adjuvanted with the novel synthetic Toll-like receptor 7/8 agonist INI-4001. We demonstrate that INI-4001 outperforms both alum and the Toll-like receptor 4 agonist INI-2002 in enhancing the immunogenicity of a dose-sparing POW-VLP vaccine in mice. INI-4001 increases the magnitude and breadth of the antibody response as measured by whole-virus ELISA, induces neutralizing antibodies measured by FRNT, reduces viral burden in the brain of infected mice measured by RT qPCR, and confers 100% protection from lethal challenge with both lineages of POWV. We show that the antibody response induced by INI-4001 is more durable than standard alum, and 80% of mice remain protected from lethal challenge 9-months post-vaccination. Lastly, we show that the protection elicited by INI-4001 adjuvanted POW-VLP vaccine is unaffected by either CD4+ or CD8+ T cell depletion and can be passively transferred to unvaccinated mice indicating that protection is mediated through humoral immunity. This study highlights the utility of novel synthetic adjuvants in VLP-based vaccines. Author summaryPowassan virus (POWV) is an emerging pathogenic tick-borne flavivirus for which there is no vaccine. Current tick-borne flavivirus vaccines are less than ideal and use formalin-inactivated virus adjuvanted with alum. These vaccines require thorough inactivation of the antigen and frequent boosting to maintain immunity. In this study, we describe the development of a POWV vaccine using Powassan virus-like-particles (POW-VLPs) adjuvanted with either of two novel Toll-like receptor (TLR) agonists, the TLR4 agonist INI-2002 or the TLR7/8 agonist INI-4001. We show that INI-4001 enhances the antibody response, reduces POWV neuroinvasion, and elicits full protection from lethal POWV infection in mice prime-boost vaccinated with low doses of POW-VLP. We further show that this protection is mediated by a humoral immune response which is both broader and more durable than a POW-VLP vaccine formulated with alum. These findings demonstrate the effectiveness of the novel synthetic TLR7/8 agonist INI-4001 as an adjuvant for low-dose VLP-based vaccines and the ability of this vaccine platform to improve upon current tick-borne flavivirus vaccine methodology.

immunology↗

bioRxiv2024

Systemic exposure to COVID-19 virus-like particles modulates firing patterns of cortical neurons in the living mouse brain

Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) causes a systemic infection that affects the central nervous system. We used virus-like particles (VLPs) to explore how exposure to the SARS-CoV-2 proteins affects brain activity patterns in wild-type (WT) mice and in mice that express the wild-type human tau protein (htau mice). VLP exposure elicited dose-dependent changes in corticosterone and distinct chemokine levels. Longitudinal two-photon microscopy recordings of primary somatosensory and motor cortex neurons that express the jGCaMP7s calcium sensor tracked modifications of neuronal activity patterns following exposure to VLPs. There was a substantial short-term increase in stimulus-evoked activity metrics in both WT and htau VLP-injected mice, while htau mice showed also increased spontaneous activity metrics and increase activity in the vehicle-injected group. Over the following weeks, activity metrics in WT mice subsided, but remained above baseline levels. For htau mice, activity metrics either remain elevated or decreased to lower levels than baseline. Overall, our data suggest that exposure to the SARS-CoV-2 VLPs leads to strong short-term disruption of cortical activity patterns in mice with long-term residual effects. The htau mice, which have a more vulnerable genetic background, exhibited more severe pathobiology that may lead to more adverse outcomes.

neuroscience↗