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Early in the SARS-CoV-2 pandemic, description of COVID-19 illness among non-hospitalized patients was limited. Data from household cohorts can help reveal the full spectrum of disease and the potential for long-term sequelae, even in non-severe disease. Daily symptom diaries were collected in a US household cohort of SARS-CoV-2 infection from April to November 2020, during the pre-COVID vaccine period. SARS-CoV-2 nasal viral loads were measured at study entry and weekly until day 21; serologic testing was performed at study entry and day 28. A subset of volunteers underwent an additional assessment 8-10 months later. Participants who met the criteria for early infection-testing antibody-negative at study entry but PCR-positive either at baseline or during follow-up-were included in this analysis (n = 143). Daily symptoms were ascertained in 143 outpatients with acute COVID-19, including 60 index cases who sought testing and 83 of their household contacts. Asymptomatic cases comprised 16% (13/83) of SARS-CoV-2 infections detected among household contacts. Among 119 persons with mild or moderate illness, the number of symptoms peaked 3 or 4 days after symptom onset. Fever and anosmia occurred in nearly half of participants. Symptom severity was associated with increased age, viral load, and cardiovascular disease. Increased BMI was associated with a higher antibody level at day 28, independent of symptom severity. Those with a higher day 28 antibody level were more likely to develop symptoms consistent with post-acute sequelae of SARS-CoV-2 (PASC), also known as long COVID-19, 8-10 months later. Fever, anosmia, as well as asymptomatic infection were common features of COVID-19 non-severe illness when the D614G variant circulated in the US, before the availability of vaccines or outpatient therapies. Antibody levels following acute infection were linked to the development of symptoms of PASC 8-10 months later.

Chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes acute febrile illness that can progress into chronic arthritis-like disease (CHIKVD) in humans. CD4 + T cells have important functions in CHIKV infection, yet the CHIKV target proteins for these CD4 + T cells are poorly characterized. Here, by stimulating PBMCs collected from individuals with chronic CHIKVD with peptides spanning the entire CHIKV proteome, we provide a comprehensive landscape of CHIKV CD4 + T cell epitopes. We identify three immunodominant regions and associated core motifs in CHIKV E1, nsP1 and CP proteins. In addition, by in silico assessment of the sequence conservation of CHIKV proteome with closely related alphaviruses, we define CHIKV epitopes conserved across arthritogenic and encephalitic viruses. Overall, our work describes CD4 + T cell targets of CHIKV in humans, thereby assisting in studying the functions of CD4 + T cells in CHIKV pathogenesis and vaccine design. Chikungunya virus (CHIKV) infects humans and causes chronic arthritic diseases, yet information on CHIKV immune epitopes is still lacking. Here the authors stimulate peripheral blood cells from CHIKV patients with a peptide pool covering the full CHIKV proteome to define CD4 + T cell epitopes as well as to map cross-reactivity with closely related alphaviruses.

Historically, DENV-4 has been rarely associated with epidemics and has been less well-studied than DENV-1 to -3. Epidemic dengue struck several South and Central American countries in 2022, with Nicaragua reporting the highest incidence. In an acute febrile illness (AFI) cohort enrolled from June to September 2022, 58 (34%) of 172 patients had PCR-confirmed dengue, of which 46 (79%) were serotyped as DENV-4. In this cohort, acute dengue, as a proportion of AFI, increased from 8% in June to a peak of 58% in August. Genome sequencing and phylogenetic analysis identified a lineage of DENV-4 Genotype IIb (GIIb) with six amino acid substitutions on the surface-exposed regions of the envelope (E) protein as compared to a reference sequence from 2005. Indeed, two of these mutations appear to be novel and located at G172E or near N174K, an antigenic epitope on domain I. Most (90%, 43/48) DENV-4 patients had pre-existing DENV IgG (secondary dengue), at the acute phase. Secondary dengue was associated with the male sex (prevalence ratio (PR)), 6.88) and being younger than 11 years of age (PR, 8.38). Further analysis showed no association between past Zika exposure and DENV-4 acute illness in older subjects (≥12 years of age). In conclusion, our study describes an epidemic of DENV-4 in León, Nicaragua, associated with a novel lineage of genotype GIIb, which contains two amino acid changes not observed in DENV-4 before 2022.

Background SARS-CoV-2, the causative agent of COVID-19, is a betacoronavirus belonging to the same genus as endemic human coronaviruses (hCoVs) OC43 and HKU1 and is distinct from alpha hCoVs 229E and NL63. In a study of adolescents in the Philippines, we evaluated seroprevalence to the hCoVs, whether pre-pandemic hCoV immunity modulated subsequent risk of SARS-CoV-2 infection, and if SARS-CoV-2 infection affected the transmission of the hCoVs. Methods From 499 individuals screened in 2021 for SARS-CoV-2 receptor binding domain (RBD) antibodies by enzyme-linked immunosorbent assay (ELISA), we randomly selected 59 SARS-CoV-2 negative and 61 positive individuals for further serological evaluation. We measured RBD and spike antibodies to the four hCoVs and SARS-CoV-2 by ELISA in samples from the same participants collected pre-pandemic (2018–2019) and mid-pandemic (2021), before COVID-19 vaccination. Results We observed over 72% seropositivity to the four hCoVs pre-pandemic. Binding antibodies increased with age to 229E and OC43, suggesting endemic circulation, while antibody levels was flat across ages for HKU1 and NL63. During the COVID-19 pandemic, antibodies increased significantly to the RBDs of OC43, NL63, and 229E and spikes of all four hCoVs in both SARS-CoV-2 negative and positive adolescents. Those aged 12–15 years old in 2021 had higher antibodies to RBD and spike of OC43, NL63, and 229E than adolescents the same age in 2019, further demonstrating intense transmission of the hCoVs during the pandemic. Conclusions We observe a limited impact of the COVID-19 pandemic on endemic hCoV transmission. This study provides insight into co-circulation of hCoVs and SARS-CoV-2.

Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous coronavirus infection, the emergence of novel variants and the presence of large zoonotic reservoirs harboring novel heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model of coronavirus disease to evaluate inactivated vaccine performance against either homologous challenge with SARS-CoV-2 or heterologous challenge with a bat-derived coronavirus that represents a potential emerging disease threat. We show that inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide can cause enhanced respiratory disease during heterologous infection, while use of an alternative adjuvant does not drive disease and promotes heterologous viral clearance. In this work, we highlight the impact of adjuvant selection on inactivated vaccine safety and efficacy against heterologous coronavirus infection. Here, Dillard and Taft-Benz et al. show in a female mouse model how different adjuvants affect inactivated vaccine-mediated protection against homologous SARS-CoV-2 and heterologous SARS-CoV-1-like coronaviruses. They find that an aluminum hydroxide-adjuvanted vaccine can increase risk of adverse outcomes during heterologous infection.

IntroductionThe conduct of clinical research is essential during public health emergencies, including COVID-19, to characterise the natural history of the infection to inform case definitions, identify risk factors for severe disease, transmission patterns, short and long-term complications and safe and effective treatments and vaccines. Policies aimed at mitigating transmission of SARS-CoV-2 proved challenging to conduct clinical research. Here, we describe the Vital Status and Outcomes of COVID-19 (VISION) study, a hybrid no-touch and low-touch clinical research protocol following participants recently infected with SARS-CoV-2.Methods and analysisIn this prospective longitudinal no-touch and low-touch observational study of recent SARS-CoV-2 infection, participants are enrolled virtually into a no-touch online primary cohort, which collects clinical information using electronic surveys. Eligible participants are able to additionally enrol into low-touch cohorts that collect biospecimens to characterise viral and immune dynamics.Ethics and disseminationThe VISION study is approved by the UNC Biomedical Institutional Review Board. Virtual enrolment coupled with hybrid no and low-touch data collection reduces barriers to participation in clinical research while allowing for an expansive investigation of the COVID-19 disease course.

Oral fluids provide ready detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and host responses. This study sought to evaluate relationships between oral virus, oral and systemic anti-SARS-CoV-2-specific antibodies, and symptoms. Oral fluids (saliva/throat wash (saliva/TW)) and serum were collected from asymptomatic and symptomatic, nasopharyngeal (NP) SARS-CoV-2 RT-qPCR+ human participants (n = 45). SARS-CoV-2 RT-qPCR and N-antigen detection by immunoblot and lateral flow assay (LFA) were performed. RT-qPCR for subgenomic RNA (sgRNA) was sequence confirmed. SARS-CoV-2-anti-S protein RBD LFA and ELISA assessed IgM and IgG responses. Structural analysis identified host salivary molecules analogous to SARS-CoV-2-N-antigen. At time of enrollment (baseline, BL), LFA-detected N-antigen in 86% of TW and was immunoblot-confirmed. However, only 3/17 were saliva/TW qPCR+ . Sixty percent of saliva and 83% of TW demonstrated persistent N-antigen at 4 weeks. N-antigen LFA signal in three anti-spike sero-negative participants suggested potential cross-detection of 4 structurally analogous salivary RNA binding proteins (alignment 19–29aa, RMSD 1–1.5 Angstroms). At enrollment, symptomatic participants demonstrated replication-associated sgRNA junctions, were IgG+ (94%/100% in saliva/TW), and IgM+ (63%/54%). At 4 weeks, SARS-CoV-2 IgG (100%/83%) and IgM (80%/67%) persisted. Oral and serum IgG correlated 100% with NP+ PCR status. Cough and fatigue severity ( p  = 0.010 and 0.018 respectively), and presence of weakness, nausea, and composite upper respiratory symptoms ( p  = 0.037, 0.005, and 0.017, respectively) were negatively associated with saliva IgM but not TW or serum IgM. Throat wash IgM levels were higher in women compared to men, although the association did not reach statistical significance (median: 290 (female) versus 0.697, p  = 0.056). Important to transmission and disease course, oral viral replication and persistence showed clear relationships with select symptoms and early oral IgM responses during early infection. N-antigen cross-reactivity may reflect mimicry of structurally analogous host proteins.

Vaccination against SARS-CoV-2 induces an immune response that is protective against severe disease in healthy populations. However, humoral and cellular immune responses in individuals with immune-mediated diseases receiving immunosuppressive medications are not well understood. We conducted a single-center, prospective observational cohort study of pediatric and adult patients with vasculitis, glomerular disease, or other immune-mediated diseases. Antibody response assessed by viral neutralization and, in a subset, cellular immunity to SARS-CoV-2 vaccination were assessed before and at time points following initial and booster vaccination. Between March 2021 and June 2022, 80 individuals with immune-mediated diseases and 12 healthy controls were enrolled and followed for a median of 11.97 months (IQR 7.64, 14.05). Following vaccination, the median percent angiotensin-converting enzyme 2 (ACE2) neutralization at V1 (1-3 months post vaccination) for patients in the immune-mediated disease cohort and healthy controls were 46.9% (IQR 0.65, 95.6) and 95.9% (IQR 94.6, 96.5), respectively. Of 26 individuals with anti-CD20 therapy exposure or laboratory evidence of B cell depletion at time of vaccination, only 11.9% had protective neutralization titers at V1. After adjustment for age, sex, BMI, race, vaccine type, and number of comorbidities, anti-CD20 exposure at time of initial vaccination remained significantly associated with a lower odds of ACE2 neutralization ≥30% at V1. The median T-ELISpot counts (RBD) at V1 for patients with immune-mediated diseases and healthy controls were comparable (16 [IQR 12, 37] and 16 [IQR 4.5, 23], respectively). Vaccination against SARS-CoV-2 during treatment with anti-CD20 antibody therapy was associated with impaired humoral immunity, but T cell responses were qualitatively preserved despite immunosuppressant exposure.

Understanding the role of mucosal immune responses in preventing coronavirus replication is essential for the development of broad-spectrum therapeutics and vaccines capable of interrupting transmission. Investigating the relationship between mucosal antibodies and viral shedding may provide critical insights into protective mechanisms against SARS-CoV-2 and inform strategies for enhancing mucosal immunity. In a subset of the larger CoVPN 5001 cohort, 143 participants from the US, Mexico, and South America were characterized as either short (<7 days), intermediate (7-21 days), or prolonged (>21 days) virus shedders based on RT-qPCR measurements over the first month of acute SARS-CoV-2 infection. We measured systemic circulating serum IgA and secretory IgA (SIgA) in serially collected nasal lavage fluids to 15 SARS-CoV-2 antigens, including spike variants, receptor binding domain (RBD), and N-terminal Domain (NTD) and evaluated the relationship between antibody titers and duration of viral shedding using multivariate and binary logistic regression modeling. We also assessed antibody responses to RBD proteins of endemic alpha and beta coronaviruses to compare variations in antibody kinetics throughout the course of infection. We found that increased serum IgA and mucosal secretory IgA antibody titers during the earliest phase of acute infection were associated with decreased viral shedding duration, with nasal IgA responses to the spike NTD being the strongest factor associated with viral shedding (adjusted p<0.1). In contrast, antibody titers against endemic human coronaviruses remained stable throughout the course of infection, consistent with a specific role for newly elicited SARS-CoV-2 antibodies in virus control. These findings demonstrate that early rises in serum and mucosal IgA titers are associated with reduced duration of viral shedding. Notably, nasal secretory IgA responses targeting the spike N-terminal domain were most strongly associated with shorter shedding, suggesting a potentially protective role for SARS-CoV-2-specific nasal IgA during acute SARS-CoV-2 infection. These results highlight the importance of mucosal immunity for limiting viral transmission and shedding, offering future insights for pan-coronavirus therapeutics and vaccine development aimed for enhancing SARS-COV-2 mucosal antibody responses.

Zika virus (ZIKV) and the 4 dengue virus (DENV) serotypes are mosquito-borne Flaviviruses that are associated with severe neuronal and hemorrhagic syndromes. The mature flavivirus infectious virion has 90 envelope (E) protein homo-dimers that pack tightly to form a smooth protein coat with icosahedral symmetry. Human antibodies that strongly neutralize ZIKV and DENVs recognize complex quaternary structure epitopes displayed on E-homo-dimers and higher order structures. The ZIKV and DENV E protein expressed as a soluble protein is mainly a monomer that does not display quaternary epitopes, which may explain the modest success with soluble recombinant E (sRecE) as a vaccine and diagnostic antigen. New strategies are needed to design recombinant immunogens that display these critical immune targets. Here we present two novel methods for building or stabilizing in vitro E-protein homo-dimers that display quaternary epitopes. In the first approach we immobilize sRecE to enable subsequent dimer generation. As an alternate method, we describe the use of human mAbs to stabilize homo-dimers in solution. The ability to produce recombinant E protein dimers displaying quaternary structure epitopes is an important advance with applications in flavivirus diagnostics and vaccine development.