Understanding immune responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection will facilitate the development of next-generation vaccines. Here, we profiled spike (S)–specific B cell responses after Omicron/BA.1 infection in messenger RNA–vaccinated donors. The acute antibody response was characterized by high levels of somatic hypermutation and a bias toward recognition of ancestral SARS-CoV-2 strains, suggesting the early activation of vaccine-induced memory B cells. BA.1 breakthrough infection induced a shift in B cell immunodominance hierarchy from the S2 subunit, which is highly conserved across SARS-CoV-2 variants of concern (VOCs), and toward the antigenically variable receptor binding domain (RBD). A large proportion of RBD-directed neutralizing antibodies isolated from BA.1 breakthrough infection donors displayed convergent sequence features and broadly recognized SARS-CoV-2 VOCs. Together, these findings provide insights into the role of preexisting immunity in shaping the B cell response to heterologous SARS-CoV-2 variant exposure.

Every breath we take contains potentially harmful pathogens or allergens. Dendritic cells (DCs), monocytes, and macrophages are essential in maintaining a delicate balance of initiating immunity without causing collateral damage to the lungs because of an exaggerated inflammatory response. To document the diversity of lung mononuclear phagocytes at steady-state, we performed bronchoscopies on 20 healthy subjects, sampling the proximal and distal airways (bronchial wash and bronchoalveolar lavage, respectively), as well as mucosal tissue (endobronchial biopsies). In addition to a substantial population of alveolar macrophages, we identified subpopulations of monocytes, myeloid DCs (MDCs), and plasmacytoid DCs in the lung mucosa. Intermediate monocytes and MDCs were highly frequent in the airways compared with peripheral blood. Strikingly, the density of mononuclear phagocytes increased upon descending the airways. Monocytes from blood and airways produced 10-fold more proinflammatory cytokines than MDCs upon ex vivo stimulation. However, airway monocytes were less inflammatory than blood monocytes, suggesting a more tolerant nature. The findings of this study establish how to identify human lung mononuclear phagocytes and how they function in normal conditions, so that dysregulations in patients with respiratory diseases can be detected to elucidate their contribution to immunity or pathogenesis.

Heterologous prime-boost immunization strategies have the potential to augment COVID-19 vaccine efficacy. We longitudinally profiled severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)–specific serological and memory B cell (MBC) responses in individuals who received either homologous (ChAdOx1:ChAdOx1) or heterologous (ChAdOx1:mRNA-1273) prime-boost vaccination. Heterologous messenger RNA (mRNA) booster immunization induced higher serum neutralizing antibody and MBC responses against SARS-CoV-2 variants of concern (VOCs) compared with that of homologous ChAdOx1 boosting. Specificity mapping of circulating B cells revealed that mRNA-1273 boost immunofocused ChAdOx1-primed responses onto epitopes expressed on prefusion-stabilized S. Monoclonal antibodies isolated from mRNA-1273–boosted participants displayed overall higher binding affinities and increased breadth of reactivity against VOCs relative to those isolated from ChAdOx1-boosted individuals. Overall, the results provide molecular insight into the enhanced quality of the B cell response induced after heterologous mRNA booster vaccination.

Multiple outbreaks of Rift Valley Fever (RVF) with devastating effects have occurred in East Africa. These outbreaks cause disease in both livestock and humans and affect poor households most severely. Communities living in areas practicing nomadic livestock movement may be at higher risk of infection. This study sought to i) determine the human exposure to Rift Valley fever virus (RVFV) in populations living within nomadic animal movement routes in Kenya; and ii) identify risk factors for RVFV infection in these communities. A cross-sectional descriptive study design was used. Samples were collected from the year 2014 to 2015 in a community-based sampling exercise involving healthy individuals aged ≥18 years from Isiolo, Tana River, and Garissa counties. In total, 1210 samples were screened by ELISA for the presence of immunoglobulin IgM and IgG antibodies against RVFV. Positive results were confirmed by plaque reduction neutralization test. Overall, IgM and IgG prevalence for all sites combined was 1.4% (95% CI 0.8–2.3%) and 36.4% (95% CI 33.8–39.2%), respectively. Isiolo County recorded a non-significant higher IgG prevalence of 38.8% than Garissa 35.9% and Tana River 32.2% (Chi square = 2.5, df = 2, p = 0.287). Males were significantly at higher risk of infection by RVFV than females (OR = 1.67, 95% CI 1.17–2.39, p<0.005). Age was significantly associated with RVFV infection (Wald Chi = 94.2, df = 5, p<0.0001). Individuals who had regular contact with cattle (OR = 1.38, 95%CI 1.01–1.89) and donkeys (OR = 1.38, 95%CI 1.14–1.67), or contact with animals through birthing (OR = 1.69, 95%CI 1.14–2.51) were significantly at a greater risk of RVFV infection than those who did not. This study demonstrated that although the Isiolo County has been classified as being at medium risk for RVF, virus infection appeared to be as prevalent in humans as in Tana River and Garissa, which have been classified as being at high risk. Populations in these counties live within nomadic livestock movement routes and therefore at risk of being exposed to the RVFV. Interventions to control RVFV infections therefore, should target communities living along livestock movement pathways. Rift Valley fever (RVF) is a neglected mosquito-borne zoonotic disease that causes major outbreaks and economic harm to human and ruminants health leading to increased poverty within affected communities. RVF is caused by RVF virus (RVFV) affecting humans and a wide range of ruminants. The virus is transmitted through bites from mosquitoes and exposure to blood, body fluids, or tissues of infected ruminants. It was first isolated in Kenya in 1930 and several outbreaks have been recorded in many countries in sub-Saharan Africa. We studied pastoralist communities living along livestock migratory routes. Migratory livestock do move long distances in search of water and pasture and may be at higher risk of exposure to RVFV. We also determined risk factors for RVFV infection by studying age, gender, contact with animals through birthing, and occupation. Prevention and control of RVFV infection can target significant risk factors to prevent spread and re-occurrence of outbreaks.

The rodent-borne hantavirus Puumala virus (PUUV) and related agents cause hemorrhagic fever with renal syndrome (HFRS) in humans. Other hantaviruses, including Andes virus (ANDV) and Sin Nombre virus, cause a distinct zoonotic disease, hantavirus cardiopulmonary syndrome (HCPS). Although these infections are severe and have substantial case fatality rates, no FDA-approved hantavirus countermeasures are available. Recent work suggests that monoclonal antibodies may have therapeutic utility. We describe here the isolation of human neutralizing antibodies (nAbs) against tetrameric Gn/Gc glycoprotein spikes from PUUV-experienced donors. We define a dominant class of nAbs recognizing the “capping loop” of Gn that masks the hydrophobic fusion loops in Gc. A subset of nAbs in this class, including ADI-42898, bound Gn/Gc complexes but not Gn alone, strongly suggesting that they recognize a quaternary epitope encompassing both Gn and Gc. ADI-42898 blocked the cell entry of seven HCPS- and HFRS-associated hantaviruses, and single doses of this nAb could protect Syrian hamsters and bank voles challenged with the highly virulent HCPS-causing ANDV and HFRS-causing PUUV, respectively. ADI-42898 is a promising candidate for clinical development as a countermeasure for both HCPS and HFRS, and its mode of Gn/Gc recognition informs the development of broadly protective hantavirus vaccines.

Understanding the presence and durability of antibodies against SARS-CoV-2 in the airways is required to provide insights into the ability of individuals to neutralize the virus locally and prevent viral spread. Here, we longitudinally assessed both systemic and airway immune responses upon SARS-CoV-2 infection in a clinically well-characterized cohort of 147 infected individuals representing the full spectrum of COVID-19 severity, from asymptomatic infection to fatal disease. In addition, we evaluated how SARS-CoV-2 vaccination influenced the antibody responses in a subset of these individuals during convalescence as compared with naive individuals. Not only systemic but also airway antibody responses correlated with the degree of COVID-19 disease severity. However, although systemic IgG levels were durable for up to 8 months, airway IgG and IgA declined significantly within 3 months. After vaccination, there was an increase in both systemic and airway antibodies, in particular IgG, often exceeding the levels found during acute disease. In contrast, naive individuals showed low airway antibodies after vaccination. In the former COVID-19 patients, airway antibody levels were significantly elevated after the boost vaccination, highlighting the importance of prime and boost vaccinations for previously infected individuals to obtain optimal mucosal protection.