Hitting SARS-CoV-2 in a new spot: A key target for therapeutic antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the spike protein, a trimeric protein complex with each monomer comprising an S1 and an S2 domain that mediate binding to host cells and membrane fusion, respectively. In addition to the receptor binding domain (RBD), S1 has an N-terminal domain (NTD). In searching for neutralizing antibodies, there has been a focus on the RBD. Chi et al. isolated antibodies from 10 convalescent patients and identified an antibody that potently neutralizes the virus but does not bind the RBD. Cryo–electron microscopy revealed the epitope as the NTD. This NTD-targeting antibody may be useful to combine with RBD-targeting antibodies in therapeutic cocktails. Science , this issue p. 650

The unprecedented coronavirus disease 2019 (COVID-19) epidemic has created a worldwide public health emergency, and there is an urgent need to develop an effective vaccine to control this severe infectious disease. Here, we find that a single vaccination with a replication-defective human type 5 adenovirus encoding the SARS-CoV-2 spike protein (Ad5-nCoV) protect mice completely against mouse-adapted SARS-CoV-2 infection in the upper and lower respiratory tracts. Additionally, a single vaccination with Ad5-nCoV protects ferrets from wild-type SARS-CoV-2 infection in the upper respiratory tract. This study suggests that the mucosal vaccination may provide a desirable protective efficacy and this delivery mode is worth further investigation in human clinical trials.

The SARS-CoV-2 Omicron variant has become the dominant SARS-CoV-2 variant around the world and exhibits immune escape to current COVID-19 vaccines to some extent due to its numerous spike mutations. Here, we evaluated the immune responses to booster vaccination with intramuscular adenovirus-vectored vaccine (Ad5-nCoV), aerosolized Ad5-nCoV, a recombinant protein subunit vaccine (ZF2001) or homologous inactivated vaccine (CoronaVac) in those who received two doses of inactivated COVID-19 vaccines 6 months prior. We found that the Ad5-nCoV booster induced potent neutralizing activity against the wild-type virus and Omicron variant, while aerosolized Ad5-nCoV generated the greatest neutralizing antibody responses against the Omicron variant at day 28 after booster vaccination, at 14.1-fold that of CoronaVac, 5.6-fold that of ZF2001 and 2.0-fold that of intramuscular Ad5-nCoV. Similarly, the aerosolized Ad5-nCoV booster produced the greatest IFNγ T-cell response at day 14 after booster vaccination. The IFNγ T-cell response to aerosolized Ad5-nCoV was 12.8-fold for CoronaVac, 16.5-fold for ZF2001, and 5.0-fold for intramuscular Ad5-nCoV. Aerosolized Ad5-nCoV booster also produced the greatest spike-specific B cell response. Our findings suggest that inactivated vaccine recipients should consider adenovirus-vectored vaccine boosters in China and that aerosolized Ad5-nCoV may provide a more efficient alternative in response to the spread of the Omicron variant.

T-cell immunity plays an important role in the control of SARS-CoV-2 and has a great cross-protective effect on the variants. The Omicron BA.1 variant contains more than 30 mutations in the spike and severely evades humoral immunity. To understand how Omicron BA.1 spike mutations affect cellular immunity, the T-cell epitopes of SARS-CoV-2 wild-type and Omicron BA.1 spike in BALB/c (H-2^d) and C57BL/6 mice (H-2^b) were mapped through IFNγ ELISpot and intracellular cytokine staining assays. The epitopes were identified and verified in splenocytes from mice vaccinated with the adenovirus type 5 vector encoding the homologous spike, and the positive peptides involved in spike mutations were tested against wide-type and Omicron BA.1 vaccines. A total of eleven T-cell epitopes of wild-type and Omicron BA.1 spike were identified in BALB/c mice, and nine were identified in C57BL/6 mice, only two of which were CD4⁺ T-cell epitopes and most of which were CD8⁺ T-cell epitopes. The A67V and Del 69-70 mutations in Omicron BA.1 spike abolished one epitope in wild-type spike, and the T478K, E484A, Q493R, G496S and H655Y mutations resulted in three new epitopes in Omicron BA.1 spike, while the Y505H mutation did not affect the epitope. These data describe the difference of T-cell epitopes in SARS-CoV-2 wild-type and Omicron BA.1 spike in H-2^b and H-2^d mice, providing a better understanding of the effects of Omicron BA.1 spike mutations on cellular immunity.

Both SARS-CoV-2 mRNA and mucosal vaccines induce protective immunity against COVID-19 but showed different immune profiles. We conducted a longitudinal head-to-head analysis of the safety and immunogenicity of the aerosolized adenovirus-vectored and mRNA COVID-19 vaccines. 450 participants were enrolled and randomly assigned into three groups to be vaccinated with an aerosolized Ad5-vectored bivalent vaccine (wild-type and BA.5, Ad5-CoV5T), an intramuscular bivalent mRNA vaccine (mbO5), and an aerosolized wild-type Ad5-vectored vaccine (Ad5-nCoV). The primary outcomes were adverse reactions within 28 days and anti-XBB.1.5-specific neutralizing antibody titers at day 28 after vaccination. The secondary outcome assessed safety within 30 min, serious adverse event within 6 months, and the persistence of anti-XBB.1.5/BA.5-specific neutralizing antibodies during the 6 months. Both the vaccines were well tolerated, but participants vaccinated with mbO5 reported more adverse reactions (73.3% mbO5 vaccinees vs. 28.7% aerosol vaccinees). No serious adverse events were recorded. The Ad5-CoV5T vaccine induced a superior anti-XBB.1.5-specific neutralizing titer than Ad5-nCoV at day 28 (geometric mean titer ratio of 1.48, 95% CI 1.12–1.97), while the mbO5 vaccine induced the highest antibody titer. The neutralizing antibodies were declined at month 6 and were similar across the three groups. In the pre-specified exploratory analysis, the mbO5 and the aerosolized vaccines induced comparable antigen-specific memory B cells but the latter stimulated higher frequency of IgA isotype and higher expression of CXCR3. This trial met the main hypothesis; the findings may provide insights for the development of the next-generation COVID-19 vaccines. Clinical Trials.gov identifier: NCT05886790.

The 2014–2016 Ebola virus epidemic in West Africa was the largest outbreak of Ebola virus disease (EVD) in history. Clarifying the influence of other prevalent diseases such as human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) will help improve treatment and supportive care of patients with EVD. We examined HIV and hepatitis C virus (HCV) antibody prevalence among suspected EVD cases from the Sierra Leone-China Friendship Biological Safety Laboratory during the epidemic in Sierra Leone. HIV and HCV antibodies were tested in 678 EVD-negative samples by enzyme-linked immunosorbent assay. A high HIV prevalence (17.6%) and low HCV prevalence (0.22%) were observed among the suspected cases. Notably, we found decreased HIV positive rates among the suspected cases over the course of the epidemic. This suggests a potentially beneficial effect of an improved public health system after assistance from the World Health Organization and other international aid organizations. This EVD epidemic had a considerable impact on the public health system and influenced the prevalence of HIV found among suspected cases in Sierra Leone, but also provided an opportunity to establish a better surveillance network for infectious diseases.