The immunology of SARS-CoV-2 infections and vaccines

SARS-CoV-2, the virus that causes COVID-19, emerged in late 2019, and was declared a global pandemic on March 11th 2020. With over 50 million cases and 1.2 million deaths around the world, to date, this pandemic represents the gravest global health crisis of our times. Thus, the race to develop a COVID-19 vaccine is an urgent global imperative. At the time of writing, there are over 165 vaccine candidates being developed, with 33 in various stages of clinical testing. In this review, we discuss emerging insights about the human immune response to SARS-CoV-2, and their implications for vaccine design. We then review emerging knowledge of the immunogenicity of the numerous vaccine candidates that are currently being tested in the clinic and discuss the range of immune defense mechanisms that can be harnessed to develop novel vaccines that confer durable protection against SARS-CoV-2. Finally, we conclude with a discussion of the potential role of a systems vaccinology approach in accelerating the clinical testing of vaccines, to meet the urgent needs posed by the pandemic.     

Association Between Average Plasma Potassium Levels and 30-day Mortality During Hospitalization in Patients with COVID-19 in Wuhan,China

Background: Coronavirus disease 2019 (COVID-19) has resulted in more than 610,000 deaths worldwide since December 2019. Given the rapid deterioration of patients'' condition before death, markers with efficient prognostic values are urgently required. During the treatment process, notable changes in plasma potassium levels have been observed among severely ill patients. We aimed to evaluate the association between average plasma potassium (K_a⁺) levels during hospitalization and 30-day mortality in patients with COVID-19.Methods: Consecutive patients with COVID-19 hospitalized in the Zhongfaxincheng branch of Tongji Hospital in Wuhan, China from February 8 to 28, 2020 were enrolled in this study. We followed patients up to 30 days after admission.Results: A total of 136 patients were included in the study. The average age was 62.1±14.6 years and 51.5% of patients were male. The median baseline potassium level was 4.3 (3.9-4.6) mmol/L and K_a⁺ level during hospitalization was 4.4 (4.2-4.7) mmol/L; the median number of times that we measured potassium was 4 (3-5). The 30-day mortality was 19.1%. A J-shaped association was observed between K_a⁺ and 30-day mortality. Multivariate Cox regression showed that compared with the reference group (K_a⁺ 4.0 to <4.5 mmol/L), 30-day mortality was 1.99 (95% confidence interval [CI]=0.54-7.35, P=0.300), 1.14 (95% CI=0.39-3.32, P=0.810), and 4.14 (95% CI=1.29-13.29, P=0.017) times higher in patients with COVID-19 who had K_a⁺ <4.0, 4.5 to <5.0, and ≥5.0 mmol/L, respectively.Conclusion: Patients with COVID-19 who had a K_a⁺ level ≥5.0 mmol/L had a significantly increased 30-day mortality compared with those who had a K_a⁺ level 4.0 to <4.5 mmol/L. Plasma potassium levels should be monitored routinely and maintained within appropriate ranges in patients with COVID-19.     

Antibody dynamics to SARS-CoV-2 in asymptomatic COVID-19 infections

Background

The missing asymptomatic COVID-19 infections have been overlooked because of the imperfect sensitivity of the nucleic acid testing (NAT). Globally understanding the humoral immunity in asymptomatic carriers will provide scientific knowledge for developing serological tests, improving early identification, and implementing more rational control strategies against the pandemic.

Measure

Utilizing both NAT and commercial kits for serum IgM and IgG antibodies, we extensively screened 11 766 epidemiologically suspected individuals on enrollment and 63 asymptomatic individuals were detected and recruited. Sixty-three healthy individuals and 51 mild patients without any preexisting conditions were set as controls. Serum IgM and IgG profiles were further probed using a SARS-CoV-2 proteome microarray, and neutralizing antibody was detected by a pseudotyped virus neutralization assay system. The dynamics of antibodies were analyzed with exposure time or symptoms onset.

Results

A combination test of NAT and serological testing for IgM antibody discovered 55.5% of the total of 63 asymptomatic infections, which significantly raises the detection sensitivity when compared with the NAT alone (19%). Serum proteome microarray analysis demonstrated that asymptomatics mainly produced IgM and IgG antibodies against S1 and N proteins out of 20 proteins of SARS-CoV-2. Different from strong and persistent N-specific antibodies, S1-specific IgM responses, which evolved in asymptomatic individuals as early as the seventh day after exposure, peaked on days from 17 days to 25 days, and then disappeared in two months, might be used as an early diagnostic biomarker. 11.8% (6/51) mild patients and 38.1% (24/63) asymptomatic individuals did not produce neutralizing antibody. In particular, neutralizing antibody in asymptomatics gradually vanished in two months.

Conclusion

Our findings might have important implications for the definition of asymptomatic COVID-19 infections, diagnosis, serological survey, public health, and immunization strategies.

     

Olfactory disorder in patients infected with SARS-CoV-2

Three (60%) of five patients with coronavirus disease 2019 (COVID-19) had olfactory disorder. Two exhibited anosmia at the onset of COVID-19, while one had hyposmia 4 days after the onset of COVID-19. All patients with olfactory disorder were completely recovered with a mean recovery length of 11.3 days.     

Better prognosis in females with severe COVID-19 pneumonia: possible role of inflammation as potential mediator

ObjectivesSex differences in COVID-19 severity and mortality have been described. Key aims of this analysis were to compare the risk of invasive mechanical ventilation (IMV) and mortality by sex and to explore whether variation in specific biomarkers could mediate this difference.MethodsThis was a retrospective, observational cohort study among patients with severe COVID-19 pneumonia. A survival analysis was conducted to compare time to the composite endpoint of IMV or death according to sex. Interaction was formally tested to compare the risk difference by sex in sub-populations. Mediation analysis with a binary endpoint IMV or death (yes/no) by day 28 of follow-up for a number of inflammation/coagulation biomarkers in the context of counterfactual prediction was also conducted.ResultsAmong 415 patients, 134 were females (32%) and 281 males (67%), median age 66 years (IQR 54–77). At admission, females showed a significantly less severe clinical and respiratory profiles with a higher PaO₂/FiO₂ (254 mmHg vs. 191 mmHg; p 0.023). By 28 days from admission, 49.2% (95% CI 39.6–58.9%) of males vs. 31.7% (17.9–45.4%) of females underwent IMV or death (log-rank p < 0.0001) and this amounted to a difference in terms of HR of 0.40 (0.26–0.63, p 0.0001). The area under the curve in C-reactive protein (CRP) over the study period appeared to explain 85% of this difference in risk by sex.DiscussionOur analysis confirms a difference in the risk of COVID-19 clinical progression by sex and provides a hypothesis for potential mechanisms leading to this. Specifically, CRP showed a predominant role to mediate the difference in risk by sex.     

SARS-CoV-2 host diversity: An update of natural infections and experimental evidence

Coronavirus disease-19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is now a pandemic threat. This virus is supposed to be spread by human to human transmission. Cellular angiotensin-converting enzyme 2 (ACE2) is the receptor of SARS-CoV-2 which is identical or similar in different species of animals such as pigs, ferrets, cats, orangutans, monkeys, and humans. Moreover, a recent study predicted that dogs might be secondary hosts during the evolution of SARS-CoV-2 from bat to human. Therefore, there is a possibility of spreading SARS-CoV-2 through domestic pets. There are now many reports of SARS-CoV-2 positive cases in dogs, cats, tigers, lion, and minks. Experimental data showed ferrets and cats are highly susceptible to SARS-CoV-2 as infected by virus inoculation and can transmit the virus directly or indirectly by droplets or airborne routes. Based on these natural infection reports and experimental data, whether the pets are responsible for SARS-CoV-2 spread to humans; needs to be deeply investigated. Humans showing clinical symptoms of respiratory infections have been undergoing for the COVID-19 diagnostic test but many infected people and few pets confirmed with SARS-CoV-2 remained asymptomatic. In this review, we summarize the natural cases of SARS-CoV-2 in animals with the latest researches conducted in this field. This review will be helpful to think insights of SARS-CoV-2 transmissions, spread, and demand for seroprevalence studies, especially in companion animals.     

The role of chest CT in management of asymptomatic SARS-CoV-2 infections: A longitudinal multi-center study in Chongqing,China

Background: Multiple societies including the Fleischner Society do not recommend that CT is routinely used in asymptomatic SARS-CoV-2 infections; however, this advice is based on the limited evidence. In this study, we aim to confirm whether it is necessary to do CT scans in SARS-CoV-2 asymptomatic infections by summarizing the longitudinal chest CT and clinical features of asymptomatic SARS-CoV-2 infections.Methods: A total of 33 individuals (14 men and 19 women) with asymptomatic SARS-CoV-2 infections were retrospectively enrolled. Clinical data of CT positive and negative groups were compared. Longitudinal chest CT scans were reviewed for CT features and analyzed for temporal change.Results: Thirty-two (97%) individuals had positive results for first RT-PCR testing. For clinical data, only monocyte count showed a significant difference between CT positive and negative groups. For first chest CT, only eighteen (54.5%) individuals had abnormal manifestations, common CT features were GGO (88.9%) and consolidation (33.3%), the median number of segments involved was 3.0 (1.0-7.5). No case in CT negative group was abnormal on the follow-up CT. Three patterns of evolution throughout series of CT were observed in CT positive group, including gradual improvement (12, 66.7%), mismatch to improvement (3, 16.7%) and mild progression to improvement (3, 16.7%). On last CT scans, most cases had radiographic improvement but residual abnormalities. Significant differences were exhibited in density, long diameter, number of lung segments involved, and percentage of consolidation between the first and last CT scans. All cases had stable conditions and finally confirmed negative for SARS-CoV-2 RT-PCR tests without developing into severe pneumonia.Conclusion: Considering poor performance of CT in screening, stable conditions during followup, and good outcomes in asymptomatic SARS-CoV-2 infections, we confirm that it is unnecessary to do CT scans in asymptomatic SARS-CoV-2 infections.     

Germline rare variants of lectin pathway genes predispose to asymptomatic SARS-CoV-2 infection in elderly individuals

PurposeEmerging evidence suggest that infection-dependent hyperactivation of complement system (CS) may worsen COVID-19 outcome. We investigated the role of predicted high impact rare variants — referred as qualifying variants (QVs) — of CS genes in predisposing asymptomatic COVID-19 in elderly individuals, known to be more susceptible to severe disease.MethodsExploiting exome sequencing data and 56 CS genes, we performed a gene-based collapsing test between 164 asymptomatic subjects (aged ≥60 years) and 56,885 European individuals from the Genome Aggregation Database. We replicated this test comparing the same asymptomatic individuals with 147 hospitalized patients with COVID-19.ResultsWe found an enrichment of QVs in 3 genes (MASP1, COLEC11, and COLEC10), which belong to the lectin pathway, in the asymptomatic cohort. Analyses of complement activity in serum showed decreased activity of lectin pathway in asymptomatic individuals with QVs. Finally, we found allelic variants associated with asymptomatic COVID-19 phenotype and with a decreased expression of MASP1, COLEC11, and COLEC10 in lung tissue.ConclusionThis study suggests that genetic rare variants can protect from severe COVID-19 by mitigating the activity of lectin pathway and prothrombin. The genetic data obtained through ES of 786 asymptomatic and 147 hospitalized individuals are publicly available at http://espocovid.ceinge.unina.it/     

HLA-B*15 predicts survival in Egyptian patients with COVID-19

Genetic differences among individuals could affect the clinical presentations and outcomes of COVID-19. Human Leukocyte Antigens are associated with COVID-19 susceptibility, severity, and prognosis. This study aimed to identify HLA-B and -C genotypes among 69 Egyptian patients with COVID-19 and correlate them with disease outcomes and other clinical and laboratory data. HLA-B and -C typing was performed using Luminex-based HLA typing kits. Forty patients (58%) had severe COVID-19; 55% of these patients died, without reported mortality in the moderate group. The alleles associated with severe COVID-19 were HLA-B*41, -B*42, -C*16, and -C*17, whereas HLA-B*15, -C*7, and -C*12 were significantly associated with protection against mortality. Regression analysis showed that HLA-B*15 was the only allele associated with predicted protection against mortality, where the likelihood of survival increased with HLA-B*15 (P < 0.001). Patient survival was less likely to occur with higher total leukocytic count, ferritin, and creatinine levels. This study provides interesting insights into the association between HLA class I alleles and protection from or severity of COVID-19 through immune response modulation. This is the first study to investigate this relationship in Egyptian patients. More studies are needed to understand how HLA class I alleles interact and affect Cytotoxic T lymphocytes and natural killer cell function.     

Cribriform pattern in lung invasive adenocarcinoma correlates with poor prognosis in a Chinese cohort

The 2011 International　Association　for　the　Study　of　Lung　Cancer/American　Thoracic　Society/European　Respiratory　Society (IASLC/ATS/ERS) lung adenocarcinoma classification and the following 2015 WHO classification have both been validated for their predictive values of histologic subtypes for prognosis. We sought to investigate the clinicopathological and prognostic significance of the cribriform pattern in lung adenocarcinomas. Histologic subtypes were evaluated in 395 patients who underwent complete resection for invasive lung adenocarcinomas between 2011 and 2013. Cribriform pattern was correlated with clinicopathological factors as well as molecular and survival data. One hundred and thirty cases (33%) were present with cribriform pattern (5–100%; mean?±?SD, 24% ± 22%). Thirty two (8%) of those were reclassified into cribriform predominant tumors. Presence of cribriform pattern (≥5%) was significantly associated with lymph/vascular invasion (P＜0.001), nodal positivity (P = 0.003), higher T stage(P = 0.005) and higher TNM stage (P = 0.001). Cribriform pattern (≥10%) was highly associated with worse disease-free survival (DFS) and overall survival (OS) (mean DFS: 42.6 months, P?<?0.001; mean OS: 64.1 months, P = 0.012). The DFS or OS for cribriform predominant tumors was similar to that for solid or micropapillary tumors. In multivariate analysis, cribriform pattern (≥10%) or cribriform predominant subtype was an independent predictor for DFS. Cribriform pattern was a specific pattern compared to other acinar patterns, presenting with more aggressive behavior. Moreover, presence of cribriform pattern was a strong predictor for worse prognosis and should be considered a high grade pattern. Our study provides further evidence for cribriform pattern to be acknowledged as an independent subtype in the future classification.     

Vascular thrombosis and vasculitis in the gastrointestinal tract are associated with poor prognosis in patients with COVID-19

Aim: To report pathologic findings in the gastrointestinal (GI) tract of coronavirus disease 2019 (COVID-19) patients. Material and Methods: we evaluated clinical and GI tract histologic findings in six COVID-19 patients that presented with GI symptoms like diarrhea, and abdominal pain. This study includes surgical resection specimens from five patients and two sets of biopsy specimens from one patient. Results: Idiopathic inflammatory bowel disease was considered in three of six cases based on clinical, radiologic, and endoscopic presentation. Histologically, the enteric mucosa had a spectrum of histologic changes, including active enteritis, chronic active enteritis, and transmural necrosis. Extensive thrombi in vessels and/or vasculitis were identified in three out of the six cases. The presence of extensive vascular thrombi is associated with poor prognosis, and the three patients deceased in a short period of time (ranges from 7-67 days, median 14 days) after admission for GI symptoms. Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) RNA was detected in bowel tissue of one case. The other three patients recovered and were discharged and free of GI symptoms (follow-up period ranges from 235 days to 270 days, median 237 days). Conclusion: COVID-19 associated enteritis may mimic Crohn’s disease clinically, radiologically and endoscopically, and these two entities can be differentiated by pathologic findings. COVID-19 patients with GI symptoms may warrant a workup to evaluate for pathologic changes, as the presence of vasculitis and microthrombi may predict poor clinical outcome.     

Upregulation of CCR4 in activated CD8+ T cells indicates enhanced lung homing in patients with severe acute SARS-CoV-2 infection

COVID-19 is a life-threatening disease leading to bilateral pneumonia and respiratory failure. The underlying reasons why a smaller percentage of patients present with severe pulmonary symptoms whereas the majority is only mildly affected are to date not well understood. Comparing the immunological phenotype in healthy donors and patients with mild versus severe COVID-19 shows that in COVID-19 patients, NK-/B-cell activation and proliferation are enhanced independent of severity. As an important precondition for effective antibody responses, T-follicular helper cells and antibody secreting cells are increased both in patients with mild and severe SARS-CoV-2 infection. Beyond this, T cells in COVID-19 patients exhibit a stronger activation profile with differentiation toward effector cell phenotypes. Importantly, when looking at the rates of pulmonary complications in COVID-19 patients, the chemokine receptor CCR4 is higher expressed by both CD4 and CD8 T cells of patients with severe COVID-19. This raises the hypothesis that CCR4 upregulation on T cells in the pathogenesis of COVID-19 promotes stronger T-cell attraction to the lungs leading to increased immune activation with presumably higher pulmonary toxicity. Our study contributes significantly to the understanding of the immunological changes during COVID-19, as new therapeutic agents, preferentially targeting the immune system, are highly warranted.