Viral and host factors associated with SARS-CoV-2 disease severity in Georgia, USA (preprint)

While SARS-CoV-2 vaccines have shown strong efficacy, their suboptimal uptake combined with the continued emergence of new viral variants raises concerns about the ongoing and future public health impact of COVID-19. We investigated viral and host factors, including vaccination status, that were associated with SARS-CoV-2 disease severity in a setting with low vaccination rates. We analyzed clinical and demographic data from 1,957 individuals in the state of Georgia, USA, coupled with viral genome sequencing from 1,185 samples. We found no difference in disease severity between individuals infected with Delta and Omicron variants among the participants in this study, after controlling for other factors, and we found no specific mutations associated with disease severity. Compared to those who were unvaccinated, vaccinated individuals experienced less severe SARS-CoV-2 disease, and the effect was similar for both variants. Vaccination within 270 days before infection was associated with decreased odds of moderate and severe outcomes, with the strongest association observed at 91-270 days post-vaccination. Older age and underlying health conditions, especially immunosuppression and renal disease, were associated with increased disease severity. Overall, this study provides insights into the impact of vaccination status, variants/mutations, and clinical factors on disease severity in SARS-CoV-2 infection when vaccination rates are low. Understanding these associations will help refine and reinforce messaging around the crucial importance of vaccination in mitigating the severity of SARS-CoV-2 disease.

SARS-CoV-2 evolution and immune escape in immunocompromised patients treated with exogenous antibodies (preprint)

Background: SARSCoV2 mutations conferring escape from neutralizing antibodies can arise in immunocompromised patients with prolonged infection, but the conditions that facilitate immune escape are still not fully understood. Methods: We characterized endogenous immune responses, within host SARSCoV2 evolution, and autologous neutralization of the viral variants that arose in five immunocompromised patients with prolonged infection and B cell deficiencies. Results: In two patients treated with the monoclonal antibody bamlanivimab, viral resistance to autologous serum arose early and persisted for several months, accompanied by ongoing evolution in the spike protein. These patients exhibited deficiencies in both T and B cell arms, and one patient succumbed to disease. In contrast, we did not observe spike mutations in immunologically important regions in patients who did not receive exogenous antibodies or who received convalescent plasma and had intact T cell responses to SARSCoV2. Conclusions: Our results underscore the potential importance of multiple factors the absence of an effective endogenous immune response, persistent virus replication, and selective pressure such as single-agent bamlanivimab in promoting the emergence of SARS-CoV-2 mutations associated with immune evasion. These findings highlight the need for larger clinical studies in immunocompromised populations to better understand the ramifications of different therapies. Our results also confirm that patients with B cell deficiencies can elicit effector T cells and may suggest an important role for T cells in controlling infection, which is relevant to vaccines and therapeutics.

Unrecognized introductions of SARS-CoV-2 into the state of Georgia shaped the early epidemic (preprint)

In early 2020, as SARS-CoV-2 diagnostic and surveillance responses ramped up, attention focused primarily on returning international travelers. Here, we build on existing studies characterizing early patterns of SARS-CoV-2 spread within the U.S. by analyzing detailed clinical, molecular, and viral genomic data from the state of Georgia through March 2020. We find evidence for multiple early introductions into Georgia, despite relatively sparse sampling. Most sampled sequences likely stemmed from a single introduction from Asia at least two weeks prior to the states first detected infection. Our analysis of sequences from domestic travelers demonstrates widespread circulation of closely-related viruses in multiple U.S. states by the end of March 2020. Our findings indicate that the early attention directed towards identifying SARS-CoV-2 in returning international travelers may have led to a failure to recognize locally circulating infections for several weeks, and points towards a critical need for rapid and broadly-targeted surveillance efforts in the future.

Reduced binding and neutralization of infection- and vaccine-induced antibodies to the B.1.351 (South African) SARS-CoV-2 variant (preprint)

The emergence of SARS-CoV-2 variants with mutations in the spike protein is raising concerns about the efficacy of infection- or vaccine-induced antibodies to neutralize these variants. We compared antibody binding and live virus neutralization of sera from naturally infected and spike mRNA vaccinated individuals against a circulating SARS-CoV-2 B.1 variant and the emerging B.1.351 variant. In acutely-infected (5-19 days post-symptom onset), convalescent COVID-19 individuals (through 8 months post-symptom onset) and mRNA-1273 vaccinated individuals (day 14 post-second dose), we observed an average 4.3-fold reduction in antibody titers to the B.1.351-derived receptor binding domain of the spike protein and an average 3.5-fold reduction in neutralizing antibody titers to the SARS-CoV-2 B.1.351 variant as compared to the B.1 variant (spike D614G). However, most acute and convalescent sera from infected and all vaccinated individuals neutralize the SARS-CoV-2 B.1.351 variant, suggesting that protective immunity is retained against COVID-19.

Infection and mRNA-1273 vaccine antibodies neutralize SARS-CoV-2 UK variant (preprint)

Antibody responses against the SARS-CoV-2 Spike protein correlate with protection against COVID-19. Serum neutralizing antibodies appear early after symptom onset following SARS-CoV-2 infection and can last for several months. Similarly, the messenger RNA vaccine, mRNA-1273, generates serum neutralizing antibodies that are detected through at least day 119. However, the recent emergence of the B.1.1.7 variant has raised significant concerns about the breadth of these neutralizing antibody responses. In this study, we used a live virus neutralization assay to compare the neutralization potency of sera from infected and vaccinated individuals against a panel of SARS-CoV-2 variants, including SARS-CoV-2 B.1.1.7. We found that both infection- and vaccine-induced antibodies were effective at neutralizing the SARS-CoV-2 B.1.1.7 variant. These findings support the notion that in the context of the UK variant, vaccine-induced immunity can provide protection against COVID-19. As additional SARS-CoV-2 viral variants continue to emerge, it is crucial to monitor their impact on neutralizing antibody responses following infection and vaccination.

Impact of SARS-CoV-2 on Seasonal Respiratory Viruses: A Tale of Two Large Metropolitan Centers in the United States (preprint)

To assess the impact of the SARS-CoV-2 pandemic on seasonal respiratory viruses, absolute case counts and viral reproductive rates from 2019-2020 were compared against previous seasons. Our findings suggest that the public health measures implemented to reduce SARS-CoV-2 transmission significantly reduced the transmission of other respiratory viruses.

Metagenomic sequencing to detect respiratory viruses in persons under investigation for COVID-19 (preprint)

We used metagenomic next-generation sequencing (mNGS) to assess the frequencies of alternative viral infections in SARS-CoV-2 RT-PCR negative persons under investigations (PUIs) (n=30) and viral co-infections in SARS-CoV-2 RT-PCR positive PUIs (n=45). mNGS identified both co-infections and alternative viral infections that were not detected by routine clinical workup.

Test Agreement Between Roche Cobas 6800 and Cepheid GeneXpert Xpress SARS-CoV-2 Assays at High Cycle Threshold Ranges (preprint)

The SARS-CoV-2 pandemic has changed the face of the globe and upended the daily lives of billions. In an effort to bring mass-testing to as many as possible, multiple diagnostic tests including molecular, antigen detection and serological assays have been rapidly developed. However, there is very little information on positive test agreement across modalities, especially for lower viral loads. Thirty-five nasopharyngeal samples that had cycle threshold (Ct) values greater than 30.0 from the Roche cobas 6800 assay were run on the Cepheid GeneXpert Xpress SARS-CoV-2 assay. Ct values ranged from 30.1 to 37.9 (mean 36.7 {+/-} 1.9) on the Roche cobas 6800 assay and 24.6 to 42.4 (mean 32.8{+/-}4.1) on the Cepheid assay. There was a bias of 0.33 {+/-} 3.21, (mean difference -1.59, 95% limits of agreement -5.97, 6.63) signifying close agreement between the 2 instruments with a high standard deviation. The close test agreement between the cobas 6800 and GeneXpert at high Ct values allows for utilization of both assays interchangeable in accordance with testing algorithms.