Examining the immunological responses to COVID-19 vaccination in multiple myeloma patients: a systematic review and meta-analysis.

BACKGROUND: Impaired immune response in multiple myeloma renders the patients vulnerable to infections, such as COVID-19, and may cause worse response to vaccines. Researchers should analyze this issue to enable the planning for special preventive measures, such as increased booster doses. Therefore, this meta-analysis aimed to evaluate the response and efficacy of COVID-19 vaccines in patients with multiple myeloma. METHODS: This meta-analysis followed PRISMA 2020 guidelines, conducting a comprehensive database search using specified keywords. Study selection involved a two-phase title/abstract and full-text screening process. Data extraction was performed by two researchers, and statistical analysis involved meta-analysis, subgroup analysis based on vaccine dosage and study time, random effects meta-regression, and heterogeneity testing using the Q test. RESULTS: The meta-analysis revealed that patients with multiple myeloma (MM) had a lower likelihood of developing detectable antibodies after COVID-19 vaccination compared to healthy controls (Log odds ratio with 95% CI: -3.34 [-4.08, -2.60]). The analysis of antibody response after different doses showed consistent lower seropositivity in MM patients (after first dose: -2.09, [-3.49, -0.69], second: -3.80, 95%CI [-4.71, -3.01], a booster dose: -3.03, [-5.91, -0.15]). However, there was no significant difference in the mean level of anti-S antibodies between MM patients and controls (Cohen's d -0.72, [-1.86, 0.43]). Evaluation of T-cell responses indicated diminished T-cell-mediated immunity in MM patients compared to controls. Seven studies reported clinical response, with breakthrough infections observed in vaccinated MM patients. CONCLUSIONS: These findings highlight the impaired humoral and cellular immune responses in MM patients after COVID-19 vaccination, suggesting the need for further investigation and potential interventions.

COVID-19 vaccine hesitancy among adults in India: A primary study based on health behavior theories and 5C psychological antecedents model.

Despite the significant success of India's COVID-19 vaccination program, a sizeable proportion of the adult population remains unvaccinated or has received a single dose of the vaccine. Despite the recommendations of the Government of India for the two doses of the COVID-19 vaccine and the precautionary booster dose, many people were still hesitant towards the COVID-19 full vaccination. Hence, this study aimed to identify the primary behavioral and psychological factors contributing to vaccine hesitancy. Cross-sectional data was collected via a multi-stage sampling design by using a scheduled sample survey in the Gorakhpur district of Uttar Pradesh, India, between 15 July 2022 to 30 September 2022. This study has utilized three health behavior models-the Health Belief Model (HBM), the Theory of Planned Behavior (TPB), and the 5C Psychological Antecedents of vaccination, and employed bivariate and multivariable binary logistic regression model to assess the level of vaccine hesitancy and predictive health behavior of the respondents. Results indicate that among the constructs of the HBM and 5C Antecedents models, "perceived benefits", "confidence" and "collective responsibility" showed a lesser likelihood of COVID-19 vaccine hesitancy. However, in the TPB model constructs, a 'negative attitude towards the vaccine' showed a four times higher likelihood of COVID-19 vaccine hesitancy. From the future policy perspective, this study suggested that addressing the issue of 'negative attitudes towards the vaccine' and increasing the trust or confidence for the vaccine through increasing awareness about the benefits of the vaccination in India may reduce vaccine hesitancy.

Evaluation of SARS-CoV-2 anti-Spike antibody levels and breakthrough infection risk among vaccinated adults in North Lebanon.

Since March 2020, the COVID-19 pandemic has swiftly propagated, triggering a competitive race among medical firms to forge vaccines that thwart the infection. Lebanon initiated its vaccination campaign on February 14, 2021. Despite numerous studies conducted to elucidate the characteristics of immune responses elicited by vaccination, the topic remains unclear. Here, we aimed to track the progression of anti-spike SARS-CoV-2 antibody titers at two-time points (T1: shortly after the second vaccination dose, T2: six months later) within a cohort of 201 adults who received Pfizer-BioNTech (BNT162b2), AstraZeneca, or Sputnik V vaccines in North Lebanon. Blood specimens were obtained from participants, and antibody titers against SARS-CoV-2 were quantified through the Elecsys-Anti-SARS-CoV-2 S assay (Roche Diagnostics, Switzerland). We used univariate analysis and multivariable logistic regression models to predict determinants influencing the decline in immune response and the occurrence of breakthrough infections among vaccinated patients. Among the 201 participants, 141 exhibited unchanging levels of antibody titers between the two sample collections, 55 displayed waning antibody titers, and only five participants demonstrated heightened antibody levels. Notably, age emerged as the sole variable significantly linked to the waning immune response. Moreover, the BNT162b2 vaccine exhibited significantly higher efficacy concerning the occurrence of breakthrough infections when compared with the AstraZeneca vaccine. Overall, our study reflected the immune status of a sample of vaccinated adults in North Lebanon. Further studies on a larger scale are needed at the national level to follow the immune response after vaccination, especially after the addition of the third vaccination dose.

Association between combination COVID-19-influenza vaccination and long COVID in middle-aged and older Europeans: A cross-sectional study.

The potential impact of combined COVID-19 and influenza vaccination on long COVID remains uncertain. In the present cross-sectional study, we aimed to investigate the plausible association between them in middle-aged and older Europeans based on the Survey of Health, Ageing, and Retirement in Europe (SHARE). A total of 1910 participants were recruited in the analyses. The study outcome was long COVID. Participants were divided into 4 groups through the self-reported status of COVID-19 and influenza vaccination. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. 1397 participants experienced long COVID. After multivariable adjustment, those vaccinated with neither COVID-19 nor influenza vaccine had higher risk of long COVID (OR, 1.72; 95% CI, 1.26-2.35) compared to those vaccinated with both vaccines. Furthermore, adding the 4 statuses of COVID-19 vaccination/influenza vaccination to conventional risk model improved risk reclassification for long COVID (continuous net reclassification improvement was 16.26% [p = .003], and integrated discrimination improvement was 0.51% [p = .005]). No heterogeneity was found in the subgroup analyses (all p-interaction ≥0.05). Our study might provide a strategy for people aged 50 and over to reduce the occurrence of long COVID, that is, to combine the use of the COVID-19 vaccine and influenza vaccines.

Cross-Reactive Antibody Responses to Coronaviruses Elicited by SARS-CoV-2 Infection or Vaccination.

BACKGROUND: The newly emerged SARS-CoV-2 possesses shared antigenic epitopes with other human coronaviruses. We investigated if COVID-19 vaccination or SARS-CoV-2 infection may boost cross-reactive antibodies to other human coronaviruses. METHODS: Prevaccination and postvaccination sera from SARS-CoV-2 naïve healthy subjects who received three doses of the mRNA vaccine (BioNTech, BNT) or the inactivated vaccine (CoronaVac, CV) were used to monitor the level of cross-reactive antibodies raised against other human coronaviruses by enzyme-linked immunosorbent assay. In comparison, convalescent sera from COVID-19 patients with or without prior vaccination history were also tested. Pseudoparticle neutralization assay was performed to detect neutralization antibody against MERS-CoV. RESULTS: Among SARS-CoV-2 infection-naïve subjects, BNT or CV significantly increased the anti-S2 antibodies against Betacoronaviruses (OC43 and MERS-CoV) but not Alphacoronaviruses (229E). The prevaccination antibody response to the common cold human coronaviruses did not negatively impact the postvaccination antibody response to SARS-CoV-2. Cross-reactive antibodies that binds to the S2 protein of MERS-CoV were similarly detected from the convalescent sera of COVID-19 patients with or without vaccination history. However, these anti-S2 antibodies do not possess neutralizing activity in MERS-CoV pseudoparticle neutralization tests. CONCLUSIONS: Our results suggest that SARS-CoV-2 infection or vaccination may potentially modulate population immune landscape against previously exposed or novel human coronaviruses. The findings have implications for future sero-epidemiological studies on MERS-CoV.

Evaluation of SARS-CoV-2 interferon gamma release assay in BNT162b2 vaccinated healthcare workers.

To predict protective immunity to SARS-CoV-2, cellular immunity seems to be more sensitive than humoral immunity. Through an Interferon-Gamma (IFN-γ) Release Assay (IGRA), we show that, despite a marked decrease in total antibodies, 94.3% of 123 healthcare workers have a positive cellular response 6 months after inoculation with the 2nd dose of BNT162b2 vaccine. Despite the qualitative relationship found, we did not observe a quantitative correlation between IFN-γ and IgG levels against SARS-CoV-2. Using stimulated whole blood from a subset of participants, we confirmed the specific T-cell response to SARS-CoV-2 by dosing elevated levels of the IL-6, IL-10 and TNF-α. Through a 20-month follow-up, we found that none of the infected participants had severe COVID-19 and that the first positive cases were only 12 months after the 2nd dose inoculation. Future studies are needed to understand if IGRA-SARS-CoV-2 can be a powerful diagnostic tool to predict future COVID-19 severe disease, guiding vaccination policies.

Integrated longitudinal multiomics study identifies immune programs associated with acute COVID-19 severity and mortality.

BACKGROUNDPatients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity.METHODSWe performed deep immunophenotyping and conducted longitudinal multiomics modeling, integrating 10 assays for 1,152 Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study participants and identifying several immune cascades that were significant drivers of differential clinical outcomes.RESULTSIncreasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, formation of neutrophil extracellular traps, and T cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma Igs and B cells and dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to failure of viral clearance in patients with fatal illness.CONCLUSIONOur longitudinal multiomics profiling study revealed temporal coordination across diverse omics that potentially explain the disease progression, providing insights that can inform the targeted development of therapies for patients hospitalized with COVID-19, especially those who are critically ill.TRIAL REGISTRATIONClinicalTrials.gov NCT04378777.FUNDINGNIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI122220); and National Science Foundation (DMS2310836).

Efficient transplacental transfer of SARS-CoV-2 antibodies between naturally exposed mothers and infants in Accra, Ghana.

We aimed to determine SARS-CoV-2 antibody seropositivity among pregnant women and the transplacental transfer efficiency of SARS-CoV-2-specific antibodies relative to malaria antibodies among SARS-CoV-2 seropositive mother-cord pairs. This cross-sectional study was conducted in Accra, Ghana, from March to May 2022. Antigen- specific IgG antibodies against SARS-CoV-2 (nucleoprotein and spike-receptor binding domain) and malarial antigens (circumsporozoite protein and merozoite surface protein 3) in maternal and cord plasma were measured by ELISA. Plasma from both vaccinated and unvaccinated pregnant women were tested for neutralizing antibodies using commercial kit. Of the unvaccinated pregnant women tested, 58.12% at antenatal clinics and 55.56% at the delivery wards were seropositive for both SARS-CoV-2 nucleoprotein and RBD antibodies. Anti-SARS-CoV-2 antibodies in cord samples correlated with maternal antibody levels (N antigen rs = 0.7155, p < 0.001; RBD rs = 0.8693, p < 0.001). Transplacental transfer of SARS-CoV-2 nucleoprotein antibodies was comparable to circumsporozoite protein antibodies (p = 0.9999) but both were higher than transfer rates of merozoite surface protein 3 antibodies (p < 0.001). SARS-CoV-2 IgG seropositivity among pregnant women in Accra is high with a boost of SARS-CoV-2 RBD-specific IgG in vaccinated women. Transplacental transfer of anti-SARS-CoV-2 and malarial antibodies was efficient, supporting vaccination of mothers as a strategy to protect infants against SARS-CoV-2.

Vaccines and the Eye: Current Understanding of the Molecular and Immunological Effects of Vaccination on the Eye.

Vaccination is a public health cornerstone that protects against numerous infectious diseases. Despite its benefits, immunization implications on ocular health warrant thorough investigation, particularly in the context of vaccine-induced ocular inflammation. This review aimed to elucidate the complex interplay between vaccination and the eye, focusing on the molecular and immunological pathways implicated in vaccine-associated ocular adverse effects. Through an in-depth analysis of recent advancements and the existing literature, we explored various mechanisms of vaccine-induced ocular inflammation, such as direct infection by live attenuated vaccines, immune complex formation, adjuvant-induced autoimmunity, molecular mimicry, hypersensitivity reactions, PEG-induced allergic reactions, Type 1 IFN activation, free extracellular RNA, and specific components. We further examined the specific ocular conditions associated with vaccination, such as uveitis, optic neuritis, and retinitis, and discussed the potential impact of novel vaccines, including those against SARS-CoV-2. This review sheds light on the intricate relationships between vaccination, the immune system, and ocular tissues, offering insights into informed discussions and future research directions aimed at optimizing vaccine safety and ophthalmological care. Our analysis underscores the importance of vigilance and further research to understand and mitigate the ocular side effects of vaccines, thereby ensuring the continued success of vaccination programs, while preserving ocular health.

Driving consistency: CEPI-Centralized Laboratory Network's conversion factor initiative for SARS-CoV-2 clinical assays used for efficacy assessment of COVID vaccines.

To date, thousands of SARS-CoV-2 samples from many vaccine developers have been tested within the CEPI-Centralized Laboratory Network. To convert data from each clinical assay to international standard units, the WHO international standard and the CEPI standard generated by the Medicines and Healthcare products Regulatory Agency were run in multiple facilities to determine the conversion factor for each assay. Reporting results in international units advances global understanding of SARS-CoV-2 immunity and vaccine efficacy, enhancing the quality, reliability, and utility of clinical assay data.

Long-term stability and immunogenicity of lipid nanoparticle COVID-19 mRNA vaccine is affected by particle size.

Messenger ribonucleic acid (mRNA) technology has been rapidly applied for the development of the COVID-19 vaccine. However, naked mRNA itself is inherently unstable. Lipid nanoparticles (LNPs) protect mRNAs from extracellular ribonucleases and facilitate mRNA trafficking. For mRNA vaccines, antigen-presenting cells utilize LNPs through uptake to elicit antigen-specific immunity. There are reports on the impact of various physical characteristics of LNPs, particularly those with sizes less than 200 nm, especially 50 to 150 nm, on the overall stability and protective efficacy of mRNA vaccines. To address this, a single change in the size of LNPs using the same mRNA stock solution was assessed for the physicochemical characterization of the resulting mRNA-LNPs vaccine, along with the evaluation of their protective efficacy. Particles of smaller sizes generally disperse more effectively in solutions, with minimized occurrence of particle precipitation and aggregation. Here, we demonstrate that the vaccine containing 80-100 nm mRNA-LNPs showed the best stability and protection at 4°C and -20°C. Furthermore, we can conclude that freezing the vaccine at -20°C is more appropriate for maintaining stability over the long term. This effort is poised to provide a scientific basis for improving the quality of ongoing mRNA vaccine endeavors and providing information on the development of novel products.

Exosome may be the next generation of promising cell-free vaccines.

Traditional vaccines have limits against some persistent infections and pathogens. The development of novel vaccine technologies is particularly critical for the future. Exosomes play an important role in physiological and pathological processes. Exosomes present many advantages, such as inherent capacity being biocompatible, non-toxic, which make them a more desirable candidate for vaccines. However, research on exosomes are in their infancy and the barriers of low yield, low purity, and weak targeting of exosomes limit their applications in vaccines. Accordingly, further exploration is necessary to improve these problems and subsequently facilitate the functional studies of exosomes. In this study, we reviewed the origin, classification, functions, modifications, separation and purification, and characterization methods of exosomes. Meanwhile, we focused on the role and mechanism of exosomes for cancer and COVID-19 vaccines.

Humoral responses to multiple SARS-CoV-2 variants after two doses of vaccine in kidney transplant patients.

Background: The COVID-19 pandemic has led to millions of fatalities globally. Kidney transplant (KT) patients, given their comorbidities and under immunosuppressant drugs, are identified as a high-risk group. Though vaccination remains pivotal for pandemic control, some studies indicate that KT exhibits diminished immune reactions to SARS-CoV-2 vaccines. Therefore, evaluating the vaccine responses in KT, especially the humoral responses against emergent variants is crucial.Methods: We developed a multiplexed SARS-CoV-2 variant protein microarray, incorporating the extracellular domain (ECD) and the receptor binding domain (RBD) of the spike proteins from the variants. This was employed to investigate the collective humoral responses after administering two doses of mRNA-1273 and AZD1222 vaccines in KT under immunosuppressive drugs and in healthy controls.Results: After two doses of either mRNA-1273 or AZD1222, the KT generally showed lower surrogate neutralizing and total antibodies against spike ECD in multiple variants compared to healthy controls. Although two doses of mRNA-1273 induced 1.5-2 fold more surrogate neutralizing and total antibodies than AZD1222 in healthy controls, the KT subjects with two doses of mRNA-1273 generally exhibited higher surrogate neutralizing but similar total antibodies against spike ECD in multiple variants. There were moderate to high correlations between the surrogate neutralizing and total antibodies against spike ECDs.Conclusion: This study offers pivotal insights into the relative vulnerability of KT concerning humoral immunity and the evolving mutations of SARS-CoV-2. Such findings are useful for evaluating vaccine responses and recommending vaccine episodes for KT.

SARS-CoV-2 strains bearing Omicron BA.1 spike replicate in C57BL/6 mice.

Introduction: SARS-CoV-2, the cause of the COVID pandemic, is an RNA virus with a high propensity to mutate. Successive virus variants, including variants of concern (VOC), have emerged with increased transmission or immune escape. The original pandemic virus and early variants replicated poorly, if at all, in mice at least partly due to a mismatch between the receptor binding domain on the viral spike protein and the murine angiotensin converting enzyme 2 (ACE2). Omicron VOC emerged in late 2021 harboring > 50 new mutations, 35 of them in the spike protein. This variant resulted in a very large wave of infections, even in the face of prior immunity, albeit being inherently less severe than earlier variants. Reflecting the lower severity reported in humans, Omicron displayed attenuated infection in hamsters and also in the K18-hACE2 mouse model. K18-hACE2 mice express both the human ACE2 as well as the endogenous mouse ACE2. Methods: Here we infected hACE2 knock-in mice that express only human ACE2 and no murine ACE2, or C57BL/6 wildtype mice with SARS-CoV-2 D614G (first-wave isolate), Delta or Omicron BA.1 variants and assessed infectivity and downstream innate immune responses. Results: While replication of SARS-CoV-2 Omicron was lower in the lungs of hACE2 knock-in mice compared with SARS-CoV-2 D614G and VOC Delta, it replicated more efficiently than the earlier variants in C57BL/6 wildtype mice. This opens the opportunity to test the effect of host genetics on SARS-CoV-2 infections in wildtype mice. As a proof of principle, we tested Omicron infection in mice lacking expression of the interferon-alpha receptor-1 (IFNAR1). In these mice we found that loss of type I IFN receptor signaling resulted in higher viral loads in the lungs were detected. Finally, using a chimeric virus of first wave SARS-CoV-2 harboring the Omicron spike protein, we show that Omicron spike increase infection of C57BL/6 wildtype mice, but non-spike genes of Omicron confer attenuation of viral replication. Discussion: Since this chimeric virus efficiently infected C57BL/6 wildtype mice, and replicated in their lungs, our findings illustrate a pathway for genetic mapping of virushost interactions during SARS-CoV-2 infection.

PRIEST: predicting viral mutations with immune escape capability of SARS-CoV-2 using temporal evolutionary information.

The dynamic evolution of the severe acute respiratory syndrome coronavirus 2 virus is primarily driven by mutations in its genetic sequence, culminating in the emergence of variants with increased capability to evade host immune responses. Accurate prediction of such mutations is fundamental in mitigating pandemic spread and developing effective control measures. This study introduces a robust and interpretable deep-learning approach called PRIEST. This innovative model leverages time-series viral sequences to foresee potential viral mutations. Our comprehensive experimental evaluations underscore PRIEST's proficiency in accurately predicting immune-evading mutations. Our work represents a substantial step in utilizing deep-learning methodologies for anticipatory viral mutation analysis and pandemic response.

Side effects of COVID-19 vaccines among Iranian healthcare workers: a retrospective cohort study.

INTRODUCTION: This study assessed the incidence and severity of side effects associated with coronavirus disease 2019 (COVID-19) vaccination among healthcare workers registered with the Medical Council of the Islamic Republic of Iran. METHODOLOGY: A retrospective cohort study was conducted on the healthcare workers focusing on the side-effects of COVID-19 vaccines from March to June 2021. Data were collected using online questionnaires. Multivariable logistic regression was used to assess the association between side effects of the vaccines and demographic variables, comorbidities, vaccine type, and history of COVID-19. RESULTS: Out of 42,018 people who were included, 55.85% reported at least one side effect after receiving the first vaccine dose. 4.59% of those with side effects sought diagnostic intervention or were referred to treatment centers. Multivariable logistic regression indicated that being a woman, higher education, having a history of COVID-19 infection, and having comorbidities increased the risk of side effects. The AstraZeneca vaccine significantly increased the risk of side effects compared to the Sputnik vaccine, while the Sinopharm vaccine decreased this risk. The risk of developing a side effect decreased with age. The risk of moderate and severe side effects was significantly associated with gender, younger age, comorbidities, and a history of COVID-19 infection. Moderate and severe side effects were less reported by those who received the Sinopharm vaccine. CONCLUSIONS: Clinical complications after COVID-19 vaccination, directly or indirectly caused by the vaccines, are common. However, the benefits of COVID-19 vaccines greatly outweigh the risk of reversible side effects, especially among the high-risk population.

Impact of vaccination on ICU admissions of hospitalized COVID-19 patients in a country with a heterologous vaccine policy.

INTRODUCTION: Vaccination against coronavirus disease-19 (COVID-19) is highly effective in preventing severe disease and mortality. Adenoviral vector and mRNA vaccines were effective against intensive care unit (ICU) admission, but the effectiveness of inactivated vaccine on ICU admission was unclear. We aimed to evaluate the effect of vaccination status on ICU admission in hospitalized COVID-19 patients in a country with heterologous vaccination policy. METHODOLOGY: This is a retrospective multicenter study conducted in three hospitals in Izmir, Turkey between 1 January 2021 and 31 March 2022. Patients aged ≥ 18 years and hospitalized due to COVID-19 were included in the study. Patients who had never been vaccinated and patients who had been vaccinated with a single dose were considered unvaccinated. A logistic regression analysis was performed for evaluating risk factors for ICU admission. RESULTS: A total of 2,110 patients were included in the final analysis. The median age was 66 years (IQR, 53-76 years) and 54% of the patients were vaccinated. During the study period, 407 patients (19.3%) were transferred to the ICU due to disease severity. Patients who were admitted to the ICU were older (median age 68 vs. 65 years, p < 0.001); and the number of unvaccinated individuals was higher among ICU patients (57% vs. 45%, p < 0.001). In multivariate regression analysis, being unvaccinated was found to be the most important independent risk factor for ICU admission with an OR of 2.06 (95% CI, 1.64-2.59). CONCLUSIONS: Vaccination against COVID-19 is effective against ICU admission and hospital mortality.

BCG activation of trained immunity is associated with induction of cross reactive COVID-19 antibodies in a BCG vaccinated population.

BACKGROUND: Pakistan is endemic to a diverse set of parasitic, mycobacterial and viral diseases. The recognition of BCG Trained Immunity (TI) led us to postulate that the continued presence of BCG-TI may play a protective role, previously reported for both infectious and noninfectious conditions. Most of the previous studies have addressed the issue of BCG-TI in the paediatric populations. This study addressed the key issue of maintenance of BCG-TI in a wider age range (adolescent and adults) to identify the strength and quality of the immune responses. OBJECTIVE: To assess the BCG-induced recall responses in healthy individuals by cytokines secreted from the TI network and its potential role in providing cross-protection against COVID-19 and other viral infections. STUDY DESIGN: In this cross-sectional study, healthy young adults and adolescents (n = 20) were recruited from 16-40 years of age, with no prior history of TB treatment, autoimmune, or chronic inflammatory condition. METHODS: BCG-induced cytokine responses were assessed using prototypic markers for cells of the TI network [macrophages [M1 (TNFα, IFNγ), M2 (IL10)], NK (IL2), Gamma delta (γδ) T (IL17, IL4)] and SARS CoV2 IgG antibodies against RBD using short-term (12 hrs.) cultures assay. RESULTS: Significant differences were observed in the magnitude of recall responses to BCG with macrophage cytokines showing the highest mean levels of TNFα (9148 pg/ml) followed by IL10 (488 pg/ml) and IFNγ (355 pg/ml). The ratio of unstimulated vs.BCG-stimulated cytokines was 132 fold higher for TNFα, 40 fold fo r IL10, and 27 fold for IFNγ. Furthermore, SARS-CoV-2 antibodies were also detected in unstimulated plasma which showed cross reactivity with BCG. CONCLUSION: The presence of cross reactive antibodies to SARS-CoV-2 and the relative ratio of pro- and anti-inflammatory cytokines secreted by activated TI cellular network may play a pivotal role in protection in the early stages of infection as observed during the COVID-19 pandemic in the younger age groups resulting in lower morbidity and mortality.