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The global SARS-CoV-2 pandemic prompted rapid development of COVID-19 vaccines. Although several vaccines have received emergency approval through various public health agencies, the SARS-CoV-2 pandemic continues. Emergent variants of concern, waning immunity in the vaccinated, evidence that vaccines may not prevent transmission and inequity in vaccine distribution have driven continued development of vaccines against SARS-CoV-2 to address these public health needs. In this report, we evaluated a novel self-amplifying replicon RNA vaccine against SARS-CoV-2 in a pigtail macaque model of COVID-19 disease. We found that this vaccine elicited strong binding and neutralizing antibody responses against homologous virus. We also observed broad binding antibody against heterologous contemporary and ancestral strains, but neutralizing antibody responses were primarily targeted to the vaccine-homologous strain. While binding antibody responses were sustained, neutralizing antibody waned to undetectable levels in some animals after six months but were rapidly recalled and conferred protection from disease when the animals were challenged 7 months after vaccination as evident by reduced viral replication and pathology in the lower respiratory tract, reduced viral shedding in the nasal cavity and lower concentrations of pro-inflammatory cytokines in the lung. Cumulatively, our data demonstrate in pigtail macaques that a self-amplifying replicon RNA vaccine can elicit durable and protective immunity to SARS-CoV-2 infection. Furthermore, these data provide evidence that this vaccine can provide durable protective efficacy and reduce viral shedding even after neutralizing antibody responses have waned to undetectable levels.

The immunological and virological events that contribute to the establishment of Zika virus (ZIKV) infection in humans are unclear. Here, we show that robust cellular innate immune responses arising early in the blood and tissues in response to ZIKV infection are significantly stronger in males and correlate with increased viral persistence. In particular, early peripheral blood recruitment of plasmacytoid dendritic cells and higher production of monocyte chemoattractant protein (MCP-1) correspond with greater viral persistence and tissue dissemination. We also identify non-classical monocytes as primary in vivo targets of ZIKV infection in the blood and peripheral lymph node. These results demonstrate the potential differences in ZIKV pathogenesis between males and females and a key role for early cellular innate immune responses in the blood in viral dissemination and ZIKV pathogenesis. The immune response to Zika virus is required to curtail the infection and avoid immunopathology, but may be involved in the associated pathophysiology. Here the authors show that viral persistence and tissue tropism is shaped by an early innate immune response in a pigtail macaque model of infection.

Mosquito-borne flaviviruses, including dengue (DENV) and Zika (ZIKV) viruses, have caused widespread epidemics in areas with high HIV prevalence, partly due to the expanded geographic range of arthropod vectors. Despite the occurrence of large flavivirus outbreaks in areas with high HIV prevalence, little is known about the effects of flavivirus infection in people living with HIV (PLWH). Here, we use a pigtail macaque model of HIV/AIDS to investigate the impact of simian immunodeficiency virus (SIV)-induced immunosuppression on ZIKV replication and pathogenesis. During acute SIV infection, peripheral ZIKV cellular targets expanded and innate immune activation increased. In vitro , peripheral blood mononuclear cells (PBMC) from SIV infected pigtail macaques were less permissive to ZIKV infection. In vivo , ZIKV viremia was delayed and ZIKV was more persistent in the gastrointestinal tissues of SIV-ZIKV co-infected animals. This persistence was associated with changes in innate cellular (monocytes, neutrophils) recruitment to the blood and tissues, reduced anti-ZIKV immunity, and sustained expression of peripheral inflammatory and innate immune genes. Collectively, these findings uniquely suggest that untreated SIV infection may promote inflammatory cellular innate responses and create a state of persistent immune activation that contributes to prolonged ZIKV viremia and persistence in the gastrointestinal tract. Furthermore, these results suggest that PLWH and other immunocompromised individuals could be at higher risk for prolonged ZIKV infection, potentially extending the window of ZIKV transmission. These insights highlight the importance of including PLWH in strategies for deploying vaccines and treatments against ZIKV.

The ongoing COVID-19 vaccine rollout is critical for reducing SARS-CoV-2 infections, hospitalizations, and deaths worldwide. Unfortunately, massive disparities exist in getting vaccines to vulnerable populations, including people living with HIV. Preliminary studies indicate that COVID-19 mRNA vaccines are safe and immunogenic in people living with HIV that are virally suppressed with potent antiretroviral therapy but may be less efficacious in immunocompromised individuals. This raises the concern that COVID-19 vaccines may be less effective in resource poor settings with limited access to antiretroviral therapy. Here, we evaluated the immunogenicity of a single dose COVID-19 replicon RNA vaccine expressing Spike protein (A.1) from SARS-CoV-2 (repRNA-CoV2S) in immunocompromised, SIV infected and immune competent, naïve pigtail macaques. Moderate vaccine-specific cellular Th1 T-cell responses and binding and neutralizing antibodies were induced by repRNA-CoV2S in SIV infected animals and naïve animals. Furthermore, vaccine immunogenicity was elicited even among the animals with the highest SIV viral burden or lowest peripheral CD4 counts prior to immunization. This study provides evidence that a SARS-CoV-2 repRNA vaccine could be employed to induce strong immunity against COVID-19 in HIV infected and other immunocompromised individuals.

Selection of a pre-clinical non-human primate (NHP) model is essential when evaluating therapeutic vaccine and treatment strategies for HIV. SIV and SHIV-infected NHPs exhibit a range of viral burdens, pathologies, and responses to combinatorial antiretroviral therapy (cART) regimens and the choice of the NHP model for AIDS could influence outcomes in studies investigating interventions. Previously, in rhesus macaques (RMs) we showed that maintenance of mucosal Th17/Treg homeostasis during SIV infection correlated with a better virological response to cART. Here, in RMs we compared viral kinetics and dysregulation of gut homeostasis, defined by T cell subset disruption, during highly pathogenic SIVΔB670 compared to SHIV-1157ipd3N4 infection. SHIV infection resulted in lower acute viremia and less disruption to gut CD4 T-cell homeostasis. Additionally, 24/24 SHIV-infected versus 10/19 SIV-infected animals had sustained viral suppression <100 copies/mL of plasma after 5 months of cART. Significantly, the more profound viral suppression during cART in a subset of SIV and all SHIV-infected RMs corresponded with less gut immune dysregulation during acute SIV/SHIV infection, defined by maintenance of the Th17/Treg ratio. These results highlight significant differences in viral control during cART and gut dysregulation in NHP AIDS models and suggest that selection of a model may impact the evaluation of candidate therapeutic interventions for HIV treatment and cure strategies.

Mosquito borne flaviviruses, including dengue (DENV) and Zika (ZIKV) viruses, have caused global epidemics in areas with high HIV prevalence due to the expanded geographic range of arthropod vectors. Despite the occurrence of large flavivirus outbreaks in countries with high HIV prevalence, there is little knowledge regarding the effects of flavivirus infection in people living with HIV (PLWH). Here, we use a pigtail macaque model of HIV/AIDS to investigate the impact of simian immunodeficiency virus (SIV)-induced immunosuppression on ZIKV replication and pathogenesis. Early acute SIV infection induced expansion of peripheral ZIKV cellular targets and increased innate immune activation and peripheral blood mononuclear cells (PBMC) from SIV infected macaques were less permissive to ZIKV infection . In SIV-ZIKV co-infected animals, we found increased persistence of ZIKV in the periphery and tissues corresponding to alterations in innate cellular (monocytes, neutrophils) recruitment to the blood and tissues, decreased anti-ZIKV immunity, and chronic peripheral inflammatory and innate immune gene expression. Collectively, these findings suggest that untreated SIV infection may impair cellular innate responses and create an environment of chronic immune activation that promotes prolonged ZIKV viremia and persistence in the gastrointestinal tract. These results suggest that PLWH or other immunocompromised individuals could be at a higher risk for chronic ZIKV replication, which in turn could increase the timeframe of ZIKV transmission. Thus, PLWH are important populations to target during the deployment of vaccine and treatment strategies against ZIKV.

The global SARS-CoV-2 pandemic prompted rapid development of COVID-19 vaccines. Although several vaccines have received emergency approval through various public health agencies, the SARS-CoV-2 pandemic continues. Emergent variants of concern, waning immunity in the vaccinated, evidence that vaccines may not prevent transmission and inequity in vaccine distribution have driven continued development of vaccines against SARS-CoV-2 to address these public health needs. In this report, we evaluated a novel self-amplifying replicon RNA vaccine against SARS-CoV-2 in a pigtail macaque model of COVID-19 disease. We found that this vaccine elicited strong binding and neutralizing antibody responses. While binding antibody responses were sustained, neutralizing antibody waned to undetectable levels after six months but were rapidly recalled and conferred protection from disease when the animals were challenged 7 months after vaccination as evident by reduced viral replication and pathology in the lower respiratory tract, reduced viral shedding in the nasal cavity and lower concentrations of pro-inflammatory cytokines in the lung. Cumulatively, our data demonstrate in pigtail macaques that a self-amplifying replicon RNA vaccine can elicit durable and protective immunity to SARS-CoV-2 infection. Furthermore, these data provide evidence that this vaccine can provide durable protective efficacy and reduce viral shedding even after neutralizing antibody responses have waned to undetectable levels. Competing Interest Statement JHE, APK, JA, PB, and DHF have equity interest in HDT Bio Corp. JHE and APK are inventors on U.S. patent application no. 62/993,307 pertaining to the LION formulation. JHE, PB, and DHF have current or previous consulting agreements with various life sciences companies. All other authors declare that they have no competing interests.

A safe, effective, and scalable vaccine is urgently needed to halt the ongoing SARS-CoV-2 pandemic. Here, we describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 copies of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain (RBD) in a highly immunogenic array and induce neutralizing antibody titers roughly ten-fold higher than the prefusion-stabilized S ectodomain trimer despite a more than five-fold lower dose. Antibodies elicited by the nanoparticle immunogens target multiple distinct epitopes on the RBD, suggesting that they may not be easily susceptible to escape mutations, and exhibit a significantly lower binding:neutralizing ratio than convalescent human sera, which may minimize the risk of vaccine-associated enhanced respiratory disease. The high yield and stability of the protein components and assembled nanoparticles, especially compared to the SARS-CoV-2 prefusion-stabilized S trimer, suggest that manufacture of the nanoparticle vaccines will be highly scalable. These results highlight the utility of robust antigen display platforms for inducing potent neutralizing antibody responses and have launched cGMP manufacturing efforts to advance the lead RBD nanoparticle vaccine into the clinic.

Category: Bunion Introduction/Purpose: There is a need to understand the rate of improvement following minimally invasive chevron akin osteotomies (MICA) for correction of hallux valgus deformity using validated patient reported outcome measures (PROMs) and whether this change is clinically meaningful in order to help counsel patients as to their progress. Methods: Between July 2014 and November 2018, data was prospectively collected from consecutive patients pre-operatively and at 6, 12, and 24 months following MICA. The primary outcome measure was the change in Manchester Oxford Foot and Ankle Questionnaire (MOXFQ) score at each timepoint following MICA. Secondary outcomes include radiographic deformity correction, and exploration of cases where PROMs did not improve following MICA. Results: 190 feet with complete PROM data at each time point, were identified from a cohort of 334 feet undergoing third generation MICA. There was a statistically significant improvement in MOXFQ score for each MOXFQ domain at each time point following MICA although the majority of the improvement was within the first 6 months. 17 feet had worse MOXFQ Index scores at the six month timepoint compared to pre-operatively. Of these feet, 82.4% (n=14) improved over time such that by two years their score had improved compared to their pre-operative score. Conclusion: There is a statistically significant improvement in MOXFQ score at every time point following MICA for hallux valgus. The majority of patients who scores are worse at 6 months following will go on to have improved function compared to their pre-operative state.

Category: Bunion; Midfoot/Forefoot Introduction/Purpose: Hallux valgus deformity correction using a third-generation Minimally Invasive Chevron Akin osteotomy technique (MICA) is becoming increasingly popular. There is limited patient reported outcome measure (PROM) outcomes for patients undergoing bilateral hallux valgus corrective MICA surgery during a single operative case. Methods: Between July 2014 and May 2018, 59 consecutive patients comprising 118 feet underwent bilateral MICA in a single operative case. 1:1 propensity score matching based on preoperative PROM assessment, age, and radiographic deformity data was carried out to match each foot in the bilateral cohort with 118 feet who had undergone unilateral MICA. The primary outcome measure was the Manchester-Oxford Foot Questionnaire (MOXFQ) which was prospectively measured pre-operatively, six months and two years post-operatively. Secondary outcomes included complication rates and radiographic deformity correction with regards to the hallux valgus angle (HVA) and inter-metatarsal angle (IMA). Results: At minimum 2 year follow up, the MOXFQ post-operative scores had significantly improved for every domain (p <0.001) in both unilateral and bilateral cohorts compared to pre-operative assessment. For all domains of the MOXFQ, there was no statistically significant difference in 6 month or two year outcomes between patients undergoing bilateral and unilateral MICA surgery (p >0.05 for all outcome measures). There was no statistically significant difference between the two cohorts in complication rate (p=>0.05) or post-operative IMA or HVA (p >0.05). Conclusion: This study demonstrates that there is no significant difference in patient reported outcome measured at two year follow-up between patients who underwent bilateral versus unilateral MICA. This study should reassure surgeons who perform bilateral hallux valgus surgery in a single case that, in the medium-term, there is no difference in clinical or radiographic PROMs compared to unilateral surgery. There are potentially positive health economic benefits of performing bilateral surgery in a single sitting if clinically indicated.