Faculty Bibliography

The efficacy of COVID-19 mRNA vaccines is high, but breakthrough infections still occur. We compared the SARS-CoV-2 genomes of 76 breakthrough cases after full vaccination with BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), or JNJ-78436735 (Janssen) to unvaccinated controls (February-April 2021) in metropolitan New York, including their phylogenetic relationship, distribution of variants, and full spike mutation profiles. The median age of patients in the study was 48 years; 7 required hospitalization and 1 died. Most breakthrough infections (57/76) occurred with B.1.1.7 (Alpha) or B.1.526 (Iota). Among the 7 hospitalized cases, 4 were infected with B.1.1.7, including 1 death. Both unmatched and matched statistical analyses considering age, sex, vaccine type, and study month as covariates supported the null hypothesis of equal variant distributions between vaccinated and unvaccinated in χ2 and McNemar tests (P > 0.1), highlighting a high vaccine efficacy against B.1.1.7 and B.1.526. There was no clear association among breakthroughs between type of vaccine received and variant. In the vaccinated group, spike mutations in the N-terminal domain and receptor-binding domain that have been associated with immune evasion were overrepresented. The evolving dynamic of SARS-CoV-2 variants requires broad genomic analyses of breakthrough infections to provide real-life information on immune escape mediated by circulating variants and their spike mutations.

Respiratory failure is associated with increased mortality in COVID-19 patients. There are no validated lower airway biomarkers to predict clinical outcome. We investigated whether bacterial respiratory infections were associated with poor clinical outcome of COVID-19 in a prospective, observational cohort of 589 critically ill adults, all of whom required mechanical ventilation. For a subset of 142 patients who underwent bronchoscopy, we quantified SARS-CoV-2 viral load, analysed the lower respiratory tract microbiome using metagenomics and metatranscriptomics and profiled the host immune response. Acquisition of a hospital-acquired respiratory pathogen was not associated with fatal outcome. Poor clinical outcome was associated with lower airway enrichment with an oral commensal (Mycoplasma salivarium). Increased SARS-CoV-2 abundance, low anti-SARS-CoV-2 antibody response and a distinct host transcriptome profile of the lower airways were most predictive of mortality. Our data provide evidence that secondary respiratory infections do not drive mortality in COVID-19 and clinical management strategies should prioritize reducing viral replication and maximizing host responses to SARS-CoV-2.

With the recent approval of highly effective coronavirus disease 2019 (COVID-19) vaccines, functional and lasting immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently under investigation as antibody levels in plasma were shown to decline during convalescence. Since the absence of antibodies does not equate to absence of immune memory, we evaluate the presence of SARS-CoV-2-specific memory B cells in convalescent individuals. Here, we report a longitudinal assessment of humoral immune responses on 32 donors up to 8 months post-symptom onset. Our observations indicate that anti-Spike and anti-receptor binding domain (RBD) immunoglobulin M (IgM) in plasma decay rapidly, whereas the reduction of IgG is less prominent. Neutralizing activity also declines rapidly when compared to Fc-effector functions. Concomitantly, the frequencies of RBD-specific IgM+ B cells wane significantly when compared to RBD-specific IgG+ B cells, which remain stable. Our results add to the current understanding of immune memory following SARS-CoV-2 infection, which is critical for secondary infection prevention and vaccine efficacy.

SARS-CoV-2 and HIV are zoonotic viruses that rapidly reached pandemic scale, causing global losses and fear. The COVID-19 and AIDS pandemics ignited massive efforts worldwide to develop antiviral strategies and characterize viral architectures, biological and immunological properties, and clinical outcomes. Although both viruses have a comparable appearance as enveloped viruses with positive-stranded RNA and envelope spikes mediating cellular entry, the entry process, downstream biological and immunological pathways, clinical outcomes, and disease courses are strikingly different. This review provides a systemic comparison of both viruses' structural and functional characteristics, delineating their distinct strategies for efficient spread.

While the standard regimen of the BNT162b2 mRNA vaccine for SARS-CoV-2 includes two doses administered 3 weeks apart, some public health authorities are spacing these doses, raising concerns about efficacy. However, data indicate that a single dose can be up to 90% effective starting 14 days post-administration. To assess the mechanisms contributing to protection, we analyzed humoral and T cell responses three weeks after a single BNT162b2 dose. We observed weak neutralizing activity elicited in SARS-CoV-2 naive individuals but strong anti-receptor binding domain and spike antibodies with Fc-mediated effector functions and cellular CD4⁺ T cell responses. In previously infected individuals, a single dose boosted all humoral and T cell responses, with strong correlations between T helper and antibody immunity. Our results highlight the potential role of Fc-mediated effector functions and T cell responses in vaccine efficacy. They also provide support for spacing doses to vaccinate more individuals in conditions of vaccine scarcity.

During the first phase of the COVID-19 epidemic, New York City rapidly became the epicenter of the pandemic in the United States. While molecular phylogenetic analyses have previously highlighted multiple introductions and a period of cryptic community transmission within New York City, little is known about the circulation of SARS-CoV-2 within and among its boroughs. We here perform phylogeographic investigations to gain insights into the circulation of viral lineages during the first months of the New York City outbreak. Our analyses describe the dispersal dynamics of viral lineages at the state and city levels, illustrating that peripheral samples likely correspond to distinct dispersal events originating from the main metropolitan city areas. In line with the high prevalence recorded in this area, our results highlight the relatively important role of the borough of Queens as a transmission hub associated with higher local circulation and dispersal of viral lineages toward the surrounding boroughs.

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.

Background: In Nigeria, a manifold genetic diversity of HIV variants exists with circulating and unique recombinant forms (CRFs and URFs) being the predominant strains. In recent years, a steady increase in URFs and clade F2 viruses was monitored through partial genome sequencing. There is a dearth of characterizing emerging URFs along the full genome, which is needed to address the challenges URFs pose towards diagnosis, treatment, and HIV-1 vaccine design. Therefore, this study describes the genetic diversity of HIV-1 CRF37-cpx variants circulating among ART-naive HIV infected individuals in Rivers State, Nigeria.
Method(s): Blood samples were collected from 106 consenting ARTnaive HIV infected individuals in Rivers State, Nigeria. The age range of the participants was 18 to 70 yrs (mean age: 45.7 yrs); 51.9% were males and 48.1% were females. Sixty (50.0%) sequences from the 106 ART-naive individuals were successfully amplified and analysed.
Result(s): Of the 60 successfully generated sequences, 3 pure HIV-1 variants/subtypes, 3 circulating recombinant forms (CRFs) and one unique recombinant forms (URFs) were identified as; A1 (23.3%), F2 (3.3%), G (18.3%), CRF02-AG (36.7%), CRF37-cpx (3.3%), CRF56-cpx (1.7%) and URF-A1F2 (13.3%). However, subtype F2 and its recombinant forms accounted for 16.6% of all sequences obtained. There was evidence of circulation of HIV-1 subtype F2, URF-A1F2, CRF37-cpx and CRF56-cpx in Nigeria, and multiple circulations of HIV-1 subtypes, with the predominance of HIV-1 CRF02-AG.
Conclusion(s): This is apparently the first report of CRF37-cpx and CRF56-cpx, and probably the second report of subtype F2 and its recombinant (URF-A1F2) in Nigeria. The occurrence of F2 and its recombinants (>16%) reflects a recent emergence of the subtype in Nigeria. Close clustering of the phylogeny signified high rate of recombination between subtypes A, G, and F2, indicating a complex and evolving pattern of circulating HIV-1 among the ART-naive participants

Background: This study describes the epidemiology and genetic diversity of HIV-1 variants circulating among HIV infected individuals in old Cross River State, Nigeria. There is an on-going need to monitor the circulating strains and the emergence of novel HIV-1 variants in the country, specifically in the understudied Southeastern regions close to Cameroon.
Method(s): Four hundred and seventeen (417) HIV-1-infected patients were enrolled in this study in the age range 4 to 72 years (average: 39.1 years), approved by the Institutional Ethics Committee. HIV-1 pol and env sequences were generated and phylogenetic analyses performed. CD4 counts were measured using the Partec CyFlow Counter. Plasma viral loads (PVL) were determined using the Abbott Real-Time HIV-1 Assay US protocol.
Result(s): The CD4 counts of the 417 study participants ranged from 5 - 2139 cells/mul (average: 455.6 cells/mul). Fifty-six percent yielded detectable and quantifiable HIV-1 RNA in the range of 20 to > 18 Mio copies/mL, including six specimen with a PVL of more than 1 million copies/mL (average: 189,518 copies/mL). Most sequences were obtained from samples with PVL > 5000 copies/mL. At this point, 60 participants were studied, 34 (56.7%) from Akwa-Ibom state and 26 (43.3%) from Cross River state. Thirty-one (31) samples, (19 from Akwa-Ibom State and 12 from Cross River State) were successfully genotyped. Subtype G predominated (35.5%), followed by URF-A1F2 (25.8%), CRF02-AG (19.4%), A1 (3.2%), B (3.2%), C (3.2%), CRF09-cpx (3.2%), CRF63-02A1 (3.2%) and URF-02A1F2 (3.2%). Unique recombinant forms (URFs) comprised a dominating group of viruses (32.3%), genotypically identified in 10 samples (8x URF-A1F2, 1x URF-02A1 and 1x URF-02A1F2). URF02-A1F2, A1, B and C were only found in females. In the same vein, URF-02A1, and CRF09-cpx were only found in males.
Conclusion(s): The preliminary results of the study indicate a complex HIV-1 diversity pattern in Old Cross Rivers State, Nigeria, and possible sex differences in subtype distribution. While subtype G was the dominating lineage, we also observed a high number of CRFs and URFs. Thus, continued molecular and clinical surveillance in diverse regions of Nigeria will reveal whether the intermixing of HIV-1 variants in Nigeria proceeds and what clinical consequences it brings in its wave

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.