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

BackgroundSARS-CoV-2 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. MethodsWe characterized endogenous immune responses, within-host SARS-CoV-2 evolution, and autologous neutralization of the viral variants that arose in five immunocompromised patients with prolonged infection and B cell deficiencies. ResultsIn 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 SARS-CoV-2. ConclusionsOur 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.

Where is Omicron? Comparison of SARS-CoV-2 RT-PCR and Antigen Test Sensitivity at Commonly Sampled Anatomic Sites Over the Course of Disease

BackgroundUpper respiratory samples for SARS-CoV-2 detection include the gold standard nasopharyngeal (NP) swab, and mid-turbinate (MT) nasal swabs, oropharyngeal (OP) swabs, and saliva. Following the emergence of the omicron (B.1.1.529) variant, limited preliminary data suggest that OP swabs or saliva samples may be more sensitive than nasal swabs, highlighting the need to understand differences in viral load across different sites. MethodsMT, OP, and saliva samples were collected from symptomatic individuals presenting for evaluation in Atlanta, GA, in January 2022. Longitudinal samples were collected from a family cohort following COVID-19 exposure to describe detection of viral targets over the course of infection. ResultsSARS-CoV-2 RNA and nucleocapsid antigen measurements demonstrated a nares-predominant phenotype in a familial cohort. A consistent dominant location for SARS-CoV-2 was not found among 54 individuals. Positive percent agreement for virus detection in MT, OP and saliva specimens were 66.7 [54.1-79.2], 82.2 [71.1-93.4], and 72.5 [60.3-84.8] by RT-PCR, respectively, and 46.2 [32.6-59.7], 51.2 [36.2-66.1], and 72.0 [59.6-84.4] by ultrasensitive antigen assay. The composite of positive MT or OP assay was not significantly different than either alone for both RT-PCR and antigen assay (PPA 86.7 [76.7-96.6] and 59.5 [44.7-74.4], respectively). ConclusionsOur data suggest that SARS-CoV-2 nucleocapsid and RNA exhibited similar kinetics and diagnostic yield in three upper respiratory sample types across the duration of symptomatic disease. Collection of OP or combined nasal and OP samples does not appear to increase sensitivity versus validated nasal sampling for rapid detection of viral antigen.

mRNA-1273 and BNT162b2 mRNA vaccines have reduced neutralizing activity against the SARS-CoV-2 Omicron variant

The BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines generate potent neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the global emergence of SARS-CoV-2 variants with mutations in the spike protein, the principal antigenic target of these vaccines, has raised concerns over the neutralizing activity of vaccine-induced antibody responses. The Omicron variant, which emerged in November 2021, consists of over 30 mutations within the spike protein. Here, we used an authentic live virus neutralization assay to examine the neutralizing activity of the SARS-CoV-2 Omicron variant against mRNA vaccine-induced antibody responses. Following the 2nd dose, we observed a 30-fold reduction in neutralizing activity against the omicron variant. Through six months after the 2nd dose, none of the sera from naive vaccinated subjects showed neutralizing activity against the Omicron variant. In contrast, recovered vaccinated individuals showed a 22-fold reduction with more than half of the subjects retaining neutralizing antibody responses. Following a booster shot (3rd dose), we observed a 14-fold reduction in neutralizing activity against the omicron variant and over 90% of boosted subjects showed neutralizing activity against the omicron variant. These findings show that a 3rd dose is required to provide robust neutralizing antibody responses against the Omicron variant.

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

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

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.