Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants.

Since the start of the COVID-19 pandemic, SARS-CoV-2 has caused millions of deaths worldwide. Although a number of vaccines have been deployed, the continual evolution of the receptor-binding domain (RBD) of the virus has challenged their efficacy. In particular, the emerging variants B.1.1.7, B.1.351 and P.1 (first detected in the UK, South Africa and Brazil, respectively) have compromised the efficacy of sera from patients who have recovered from COVID-19 and immunotherapies that have received emergency use authorization1-3. One potential alternative to avert viral escape is the use of camelid VHHs (variable heavy chain domains of heavy chain antibody (also known as nanobodies)), which can recognize epitopes that are often inaccessible to conventional antibodies4. Here, we isolate anti-RBD nanobodies from llamas and from mice that we engineered to produce VHHs cloned from alpacas, dromedaries and Bactrian camels. We identified two groups of highly neutralizing nanobodies. Group 1 circumvents antigenic drift by recognizing an RBD region that is highly conserved in coronaviruses but rarely targeted by human antibodies. Group 2 is almost exclusively focused to the RBD-ACE2 interface and does not neutralize SARS-CoV-2 variants that carry E484K or N501Y substitutions. However, nanobodies in group 2 retain full neutralization activity against these variants when expressed as homotrimers, and-to our knowledge-rival the most potent antibodies against SARS-CoV-2 that have been produced to date. These findings suggest that multivalent nanobodies overcome SARS-CoV-2 mutations through two separate mechanisms: enhanced avidity for the ACE2-binding domain and recognition of conserved epitopes that are largely inaccessible to human antibodies. Therefore, although new SARS-CoV-2 mutants will continue to emerge, nanobodies represent promising tools to prevent COVID-19 mortality when vaccines are compromised.

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants.

Here we report on the antibody and memory B cell responses of a cohort of 20 volunteers who received the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccine against SARS-CoV-21-4. Eight weeks after the second injection of vaccine, volunteers showed high levels of IgM and IgG anti-SARS-CoV-2 spike protein (S) and receptor-binding-domain (RBD) binding titre. Moreover, the plasma neutralizing activity and relative numbers of RBD-specific memory B cells of vaccinated volunteers were equivalent to those of individuals who had recovered from natural infection5,6. However, activity against SARS-CoV-2 variants that encode E484K-, N501Y- or K417N/E484K/N501-mutant S was reduced by a small-but significant-margin. The monoclonal antibodies elicited by the vaccines potently neutralize SARS-CoV-2, and target a number of different RBD epitopes in common with monoclonal antibodies isolated from infected donors5-8. However, neutralization by 14 of the 17 most-potent monoclonal antibodies that we tested was reduced or abolished by the K417N, E484K or N501Y mutation. Notably, these mutations were selected when we cultured recombinant vesicular stomatitis virus expressing SARS-CoV-2 S in the presence of the monoclonal antibodies elicited by the vaccines. Together, these results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid a potential loss of clinical efficacy.

Comparison of Face-Touching Behaviors Before and During the Coronavirus Disease 2019 Pandemic.

Importance: There is insufficient evidence on the efficacy of masks in the general population for the prevention of coronavirus disease 2019 (COVID-19) in public areas. Therefore, it is imperative to investigate the association of mandatory mask-wearing policies with behaviors associated with the transmission of COVID-19. Objective: To assess the association of mask wearing with face-touching behavior among the general population in public areas. Design, Setting, and Participants: This cross-sectional study used videos recorded in public transportation stations, streets, and parks among the general population in China, Japan, South Korea, Western Europe (ie, England, France, Germany, Spain, and Italy), and the US to analyze mask-wearing and face-touching behavior in public areas. Videos before the COVID-19 pandemic were defined as those recorded from January 2018 to October 2019, and those during the COVID-19 pandemic were defined as those recorded during February 2020 to March 2020 in China, Japan, and South Korea and during March 2020 in Western Europe and the US. Individuals who clearly displayed their face and face-touching behavior were included, and those whose behaviors were influenced by filming or public events were excluded. Exposures: Mandatory mask-wearing policies enacted at various time points in China, Japan, South Korea, Western Europe, and the US. Main Outcomes and Measures: Proportion of individuals wearing masks and incidence of face touching. Results: This study included 4699 individuals before the COVID-19 pandemic and 2887 individuals during the pandemic. During the periods studied, mask wearing increased in all regions except the US, from 20 of 1745 individuals (1.1%) to 1090 of 1097 individuals (99.4%) in mainland China (P < .001), 44 of 1422 individuals (3.1%) to 346 of 893 individuals (38.7%) in Japan (P < .001), 6 of 717 individuals (0.8%) to 277 of 324 individuals (85.5% ) in South Korea (P < .001), 1 of 546 individuals (0.2%) to 6 of 379 individuals (1.6%) in Western Europe (P = .02), and 1 of 269 individuals (0.4%) to 4 of 194 individuals (2.1%) in the US (P = .17). Surgical masks were predominant in China (989 masks [89.1%]), and fabric masks were predominant in the other regions (Japan: 371 masks [95.1%]; South Korea: 240 masks [84.8%]; Western Europe: 6 masks [85.7%]; US: 5 masks [100%]). Face-touching behaviors decreased from before COVID-19 to during COVID-19 among individuals in China (72 incidences of 1745 observations [4.1%] to 12 incidences of 1097 observations [1.1%]; P < .001), South Korea (80 incidences of 717 observations [11.2%] to 7 incidences of 324 observations [2.2%]; P < .001), and Europe (62 incidences of 546 observations [11.4%] to 23 incidences of 379 observations [6.1%]; P = .01). Logistic regression found that mask wearing was associated with a reduction in face touching in China (odds ratio [OR], 3.91; 95% CI, 2.11-7.24) and South Korea (OR, 6.69; 95% CI, 2.69-16.69) and of touching the nose, mouth, and eyes (China: OR, 8.60; 95% CI, 2.65-27.86; South Korea: OR, 29.27; 95% CI, 1.79-478.22). Conclusions and Relevance: The findings of this cross-sectional study suggest that mandatory mask-wearing policies were associated with increased mask wearing during the COVID-19 pandemic. Mask wearing was associated with reduced face-touching behavior, especially touching of the eyes, nose, and mouth, which may prevent contact transmission of COVID-19 among the general population in public areas.