Faculty Bibliography

Despite vaccines, rapidly mutating viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to threaten human health due to an impaired immunoregulatory pathway and a hyperactive immune response. Our understanding of the local immune mechanisms used by tissue-resident macrophages to safeguard the host from excessive inflammation during SARS-CoV-2 infection remains limited. Here, we found that nerve- and airway-associated interstitial macrophages (NAMs) are required to control mouse-adapted SARS-CoV-2 (MA-10) infection. Control mice restricted lung viral distribution and survived infection, whereas NAM depletion enhanced viral spread and inflammation and led to 100% mortality. Mechanistically, type I interferon receptor (IFNAR) signaling by NAMs was critical for limiting inflammation and viral spread, and IFNAR deficiency in CD169⁺ macrophages mirrored NAM-depleted outcomes and abrogated their expansion. These findings highlight the essential protective role of NAMs in regulating viral spread and inflammation, offering insights into SARS-CoV-2 pathogenesis and underscoring the importance of NAMs in mediating host immunity and disease tolerance.

In May 2023 the World Health Organization (WHO) declared the end of COVID-19 as a public health emergency. Seroprevalence studies performed in African countries, such as Cameroon, depicted a much higher COVID-19 burden than reported by the WHO. To better understand humoral responses kinetics following infection, we enrolled 333 participants from Yaoundé, Cameroon between March 2020 and January 2022. We measured the levels of antibodies targeting the SARS-CoV-2 receptor-binding-domain (RBD) and the Spike glycoproteins of Delta, Omicron BA.1 and BA.4/5 and the common cold coronavirus HCoV-OC43. We also evaluated plasma capacity to neutralize authentic SARS-CoV-2 virus and to mediate Antibody-Dependent Cellular Cytotoxicity (ADCC). Most individuals mounted a strong antibody response against SARS-CoV-2 Spike. Plasma neutralization waned faster than anti-Spike binding and ADCC. We observed differences in humoral responses by age and circulating variants. Altogether, we show a global overview of antibody dynamics and functionality against SARS-CoV-2 in Cameroon.

UNLABELLED:The 2022 global outbreak of clade IIb mpox was the first major outbreak of mpox outside of African nations. To control the outbreak, public health officials began vaccination campaigns using the third-generation orthopoxvirus vaccine modified vaccinia Ankara from Bavarian Nordic (MVA-BN). Prior to this outbreak, the durability of monkeypox virus (MPXV)-specific immunity induced by MVA-BN was poorly understood. In 2022, we launched the New York City Observational Study of Mpox Immunity (NYC OSMI, NCT05654883), a longitudinal study of 171 participants comprising MVA-BN vaccines and mpox convalescent individuals. Peripheral blood sampling was performed at intervals including prior to vaccination, after one dose, and after the second dose. MVA-BN vaccinees with and without a history of smallpox vaccination demonstrated detectable MPXV-specific memory B cells at 1-year post-vaccination. Additionally, MVA-BN increased MPXV neutralizing titers in smallpox vaccine-naïve vaccinees, with a comparable maximum titer reached in naïve and smallpox vaccine-experienced vaccinees. However, neutralizing titers returned to baseline within 5-7 months for naïve individuals, while remaining elevated in those with prior smallpox vaccination. Both naïve and experienced individuals generated robust IgG responses against MPXV H3 and A35, but naïve vaccinees' IgG responses showed lower avidity than experienced vaccinees. These data highlight a low avidity antibody response elicited by MVA-BN that is short-lived in naïve vaccinees. This work supports the need for long-term studies on protection induced by MVA-BN, including the potential need for booster doses as well as the development of next-generation orthopoxvirus vaccines. IMPORTANCE/OBJECTIVE:The ongoing outbreaks of mpox demonstrate the continuing threat of orthopoxviruses to global health. While previous orthopoxvirus vaccines generated lifelong antibody and cellular immunity, we show here that the current mpox vaccine, MVA-BN or JYNNEOS, fails to induce durable antibody immunity in individuals with no prior smallpox vaccination. This raises the important question of whether MVA-BN vaccinees have long-term protection from mpox. Our work highlights the need for further studies into the durability of protection generated by MVA-BN as well as whether subsequent booster doses are necessary to maintain protection.

Early antibody therapy can prevent severe SARS-CoV-2 infection (COVID-19). However, the effectiveness of COVID-19 convalescent plasma (CCP) therapy in treating severe COVID-19 remains inconclusive. To test a hypothesis that some CCP units are associated with a coagulopathy hazard in severe disease that offsets its benefits, we tracked 304 CCP units administered to 414 hospitalized COVID-19 patients to assess their association with the onset of unfavorable post-transfusion D-dimer trends. CCP recipients with increasing or persistently elevated D-dimer trajectories after transfusion experienced higher mortality than those whose D-dimer levels were persistently low or decreasing after transfusion. Within the CCP donor-recipient network, recipients with increasing or persistently high D-dimer trajectories were skewed toward association with a minority of CCP units. In in vitro assays, CCP from "higher-risk" units had higher cross-reactivity with the spike protein of human seasonal betacoronavirus OC43. "Higher-risk" CCP units also mediated greater Fcγ receptor IIa signaling against cells expressing SARS-CoV-2 spike compared with "lower-risk" units. This study finds that post-transfusion activation of coagulation pathways during severe COVID-19 is associated with specific CCP antibody profiles and supports a potential mechanism of immune complex-activated coagulopathy.

COVID-19 vaccines were developed at unparalleled speed, but racial disparities persist in vaccine uptake. This is a cross-sectional survey that was conducted in mid-2021 in ambulatory clinics across Brooklyn, New York. The objectives of the study were to assess: knowledge of COVID-19, healthcare communication and access, attitudes including trust in the process of vaccine development and mistrust due to racial discrimination, and to determine the relationship of the above to vaccine receipt. 58 respondents self-identified as Black non-Hispanic and completed the survey: the majority were women (79%), <50 years old (65%), employed (66%), and had annual household income <$75,000 (59%). The majority reported having some health insurance (97%) and a regular place of healthcare (95%). 60% of respondents reported COVID-19 vaccination receipt. A significant percentage of the vaccinated group compared to the unvaccinated group scored higher on knowledge questions (91% vs. 65%; p = 0.018), felt it was important that others in the community get vaccinated (89% vs. 65%, p = 0.04), and trusted vaccine safety (86% vs. 35%; p < 0.0001) and effectiveness (88% vs. 48%; p < 0.001). The unvaccinated group reported a lower annual household income of <$75,000 (72% vs. 50%; p = 0.0002) and also differed by employment status (p = 0.04). Majority in both groups agreed that racial discrimination interferes with healthcare (78%). In summary, unvaccinated Black non-Hispanic respondents report significant concerns about vaccine safety and efficacy and have greater mistrust in the vaccine development process. The relationship between racial discrimination, mistrust, and vaccine hesitancy needs further study in order to improve vaccine uptake in this population.

INTRODUCTION/UNASSIGNED:Mounting evidence indicates that an individual's humoral adaptive immune response plays a critical role in the setting of SARS-CoV-2 infection, and that the efficiency of the response correlates with disease severity. The relationship between the adaptive immune dynamics in the lower airways with those in the systemic circulation, and how these relate to an individual's clinical response to SARS-CoV-2 infection, are less understood and are the focus of this study. MATERIAL AND METHODS/UNASSIGNED:We investigated the adaptive immune response to SARS-CoV-2 in paired samples from the lower airways and blood from 27 critically ill patients during the first wave of the pandemic (median time from symptom onset to intubation 11 days). Measurements included clinical outcomes (mortality), bronchoalveolar lavage fluid (BALF) and blood specimen antibody levels, and BALF viral load. RESULTS/UNASSIGNED:While there was heterogeneity in the levels of the SARS-CoV-2-specific antibodies, we unexpectedly found that some BALF specimens displayed higher levels than the paired concurrent plasma samples, despite the known dilutional effects common in BALF samples. We found that survivors had higher levels of anti-spike, anti-spike-N-terminal domain and anti-spike-receptor-binding domain IgG antibodies in their BALF (p<0.05), while there was no such association with antibody levels in the systemic circulation. DISCUSSION/UNASSIGNED:Our data highlight the critical role of local adaptive immunity in the airways as a key defence mechanism against primary SARS-CoV-2 infection.

BACKGROUND:Chronic inflammation persists in some people living with HIV (PLWH) during antiretroviral therapy and is associated with premature aging. The gp120 subunit of HIV-1 envelope sheds and can be detected in plasma, showing immunomodulatory properties even in the absence of detectable viremia. We evaluated whether plasmatic soluble gp120 (sgp120) and a family of gp120-specific anti-cluster A antibodies, linked to CD4 depletion in vitro, contribute to chronic inflammation, immune dysfunction, and sub-clinical cardiovascular disease in participants of the Canadian HIV and Aging cohort (CHACS) with undetectable viremia. METHODS:Cross-sectional assessment of sgp120 and anti-cluster A antibodies was performed in 386 individuals from CHACS. Their association with pro-inflammatory cytokines and subclinical coronary artery disease was assessed using linear regression models. RESULTS:High levels of sgp120 and anti-cluster A antibodies inversely correlated with CD4 count and CD4:CD8 ratio. The presence of sgp120 was associated with increased levels of IL-6. In participants with detectable atherosclerotic plaque and detectable sgp120, anti-cluster A antibodies and their combination with sgp120 levels correlated positively with the total volume of atherosclerotic plaques. CONCLUSIONS:sgp120 may act as a pan toxin causing immune dysfunction and sustained inflammation in a subset of PLWH, contributing to the development of premature comorbidities.

The recombinant SARS-CoV-2 Omicron XBB.1.5 variant was first detected in New York City (NYC) and rapidly became the predominant variant in the area by early 2023. The increased occurrence of circulating variants within the SARS-CoV-2 XBB-sublineage prompted the modification of COVID-19 mRNA vaccines by Moderna and Pfizer-BioNTech. This update, implemented in mid-September 2023, involved the incorporation of a monovalent XBB.1.5 component. Considering that NYC probably played a central role in the emergence of the XBB.1.5 variant, we conducted phylogeographic analysis to investigate the emergence and spread of this variant in the metropolitan area. Our analysis confirms that XBB.1.5 emerged within or near the NYC area and indicates that XBB.1.5 had a diffusion velocity similar to that of the variant Alpha in the same study area. Additionally, the analysis of 2,392 genomes collected in the context of the genomic surveillance program at NYU Langone Health system showed that there was no increased proportion of XBB.1.5, relative to all cocirculating variants, in the boosted compared to unvaccinated individuals. This study provides a comprehensive description of the emergence and dissemination of XBB.1.5.

From the perspective of developing relevant interventions for treating HIV and controlling its spread, it is particularly important to comprehensively understand the underlying diversity of the virus, especially in countries where the virus has been present and evolving since the cross-species transmission event that triggered the global pandemic. Here, we generate and phylogenetically analyse sequences derived from the gag-protease (2010 bp; n = 115), partial integrase (345 bp; n = 36), and nef (719 bp; n = 321) genes of HIV-1 group M (HIV-1M) isolates sampled between 2000 and 2022 from two cosmopolitan cities and 40 remote villages of Cameroon. While 52.4% of all sequenced viruses belonged to circulating recombinant form (CRF) 02_AG (CRF02_AG), the remainder were highly diverse, collectively representing seven subtypes and sub-subtypes, eight CRFs, and 36 highly divergent lineages that fall outside the established HIV-1M classification. Additionally, in 77 samples for which at least two genes were typed, 31% of the studied viruses apparently had fragments from viruses belonging to different clades. Furthermore, we found that the distribution of HIV-1M populations is similar between different regions of Cameroon. In contrast, HIV-1M demographics in Cameroon differ significantly from those in its neighbouring countries in the Congo Basin (CB). In phylogenetic trees, viral sequences cluster according to the countries where they were sampled, suggesting that while there are minimal geographical or social barriers to viral dissemination throughout Cameroon, there is strongly impeded dispersal of HIV-1M lineages between Cameroon and other locations of the CB. This suggests that the apparent stability of highly diverse Cameroonian HIV-1M populations may be attributable to the extensive mixing of human populations within the country and the concomitant trans-national movements of major lineages with very similar degrees of fitness; coupled with the relatively infrequent inter-national transmission of these lineages from neighbouring countries in the CB.