Inactivated COVID-19 vaccines: potential concerns of antibody-dependent enhancement and original antigenic sin.

Inactivated vaccine is one of the platforms employed in COVID-19 vaccines. Inactivated vaccines have been associated with concerns of antibody-dependent enhancement (ADE) and original antigenic sin (OAS), which are related to non-neutralising or poorly neutralising antibodies against the pathogen. Since inactivated COVID-19 vaccines use whole-SARS-CoV-2 virus as the immunogen, they are expected to generate antibodies against non-spike structural proteins, which are highly conservative across variants of SARS-CoV-2. These antibodies against non-spike structural proteins have found to be largely non-neutralising or poorly neutralising in nature. Hence, inactivated COVID-19 vaccines could possibly be associated with ADE and OAS, especially as novel variants emerge. This article explores the potential concern of ADE and OAS in the context of inactivated COVID-19 vaccine, and outlines the future research directions.

Vaccination with the Omicron spike RBD boosts broadly neutralizing antibody levels and confers sustained protection even after acquiring immunity to the original antigen.

The immune evasion of SARS-CoV-2 Omicron variants caused by multiple amino acid replacements in the receptor-binding domain (RBD) of spike protein wanes the effectiveness of antibodies elicited by current SARS-CoV-2 booster vaccination. The vaccines that target Omicron strains have been recently developed, however, there has been a concern yet to be addressed regarding the negative aspect of the immune response known as original antigenic sin. Here we demonstrate that the breadth of neutralizing antibodies against SARS-CoV-2 variants is barely elicited by immunizing monovalent viral antigens via vaccination or natural infection in mice and human subjects. However, vaccination of Omicron BA.1 RBD to pre-immunized mice with the original RBD conferred sustained neutralizing activity to BA.1 and BA.2 not only original pseudoviruses. The acquisition of neutralizing antibody breadth was further confirmed in vaccinated-then-Omicron convalescent human sera in which neutralizing activity against BA.1 and BA.2 pseudoviruses was highly induced. Thus, our data suggest that Omicron-specific vaccines or the infection with Omicron viruses can boost potent neutralizing antibodies to the Omicron variants even in the host pre-vaccinated with the original antigen.

Pre-Pandemic Cross-Reactive Immunity against SARS-CoV-2 among Central and West African Populations.

For more than two years after the emergence of COVID-19 (Coronavirus Disease-2019), significant regional differences in morbidity persist. These differences clearly show lower incidence rates in several regions of the African and Asian continents. The work reported here aimed to test the hypothesis of a pre-pandemic natural immunity acquired by some human populations in central and western Africa, which would, therefore, pose the hypothesis of an original antigenic sin with a virus antigenically close to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). To identify such pre-existing immunity, sera samples collected before the emergence of COVID-19 were tested to detect the presence of IgG reacting antibodies against SARS-CoV-2 proteins of major significance. Sera samples from French blood donors collected before the pandemic served as a control. The results showed a statistically significant difference of antibodies prevalence between the collected samples in Africa and the control samples collected in France. Given the novelty of our results, our next step consists in highlighting neutralizing antibodies to evaluate their potential for pre-pandemic protective acquired immunity against SARS-CoV-2. In conclusion, our results suggest that, in the investigated African sub-regions, the tested populations could have been potentially and partially pre-exposed, before the COVID-19 pandemic, to the antigens of a yet non-identified Coronaviruses.

SARS-CoV-2 infections elicit higher levels of original antigenic sin antibodies compared with SARS-CoV-2 mRNA vaccinations.

It is important to determine if severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and SARS-CoV-2 mRNA vaccinations elicit different types of antibodies. Here, we characterize the magnitude and specificity of SARS-CoV-2 spike-reactive antibodies from 10 acutely infected health care workers with no prior SARS-CoV-2 exposure history and 23 participants who received SARS-CoV-2 mRNA vaccines. We found that infection and primary mRNA vaccination elicit S1- and S2-reactive antibodies, while secondary vaccination boosts mostly S1 antibodies. Using absorption assays, we found that SARS-CoV-2 infections elicit a large proportion of original antigenic sin-like antibodies that bind efficiently to the spike of common seasonal human coronaviruses but poorly to the spike of SARS-CoV-2. In converse, vaccination modestly boosts antibodies reactive to the spike of common seasonal human coronaviruses, and these antibodies cross-react more efficiently to the spike of SARS-CoV-2. Our data indicate that SARS-CoV-2 infections and mRNA vaccinations elicit fundamentally different antibody responses.

Pre-Vaccine Antibodies Against Seasonal Betacoronaviruses Are Associated with Decreased Antibody Response to SARS-CoV-2 mRNA Vaccination in Solid Organ Transplant Recipients

Purpose: The impact of antigenic imprinting, when immune memory of one antigen influences the response to subsequent similar antigens, on the antibody response in solid organ transplant recipients (SOTRs) after SARS-CoV-2 vaccination is currently unknown. This study examines the relationship between seasonal coronaviruses (sCoV) and SARS-CoV-2 antibody levels pre- and post-vaccination in SOTRs. Method(s): Plasma from 52 SOTRs pre- and post-SARS-CoV-2 vaccination (2 doses, mRNA) was analyzed using the Meso Scale Diagnostic Coronavirus Panel 3 (an electrochemiluminescence detection-based multiplexed sandwich immunoassay) for IgG antibodies against alpha sCoVs (229E, NL63), beta sCoVs (HKU1, OC43), and SARS-CoV-2 spike proteins. Changes in IgG titers were determined by paired Wilcoxon rank-sum tests. Spearman correlation analysis was used to determine associations between pre-vaccination anti-sCoVs and post-vaccination anti-SARS-CoV-2 IgG. Result(s): Vaccination increased both anti-SARS-CoV-2 (fold change (FC) 1.9, p<0.001) and anti-beta sCoV (HKU1 [FC 0.05, p<0.001], OC43 [FC 0.8, p<0.001]) IgG titers in SOTRs, but did not increase anti-alpha sCoV IgG. Furthermore, prevaccination anti-beta sCoV (HKU1 [rho= -0.3, p=0.03], OC43 [rho= -0.3, p<0.03]) IgG titers were negatively correlated with post-vaccination anti-SARS-CoV-2 IgG. Conclusion(s): These exploratory findings suggest that prior exposure to seasonal betacoronaviruses may lead to antigenic imprinting in SOTRs that negatively impacts the antibody response to vaccination against the novel pandemic betacoronavirus, SARS-CoV-2.

A comprehensive review of BBV152 vaccine development, effectiveness, safety, challenges, and prospects.

The world has responded to the COVID-19 pandemic with unprecedented speed and vigor in the mass vaccination campaigns, targeted to reduce COVID-19 severity and mortality, reduce the pressure on the healthcare system, re-open society, and reduction in disease mortality and morbidity. Here we review the preclinical and clinical development of BBV152, a whole virus inactivated vaccine and an important tool in the fight to control this pandemic. BBV152, formulated with a TLR7/8 agonist adjuvant generates a Th1-biased immune response that induces high neutralization efficacy against different SARS-CoV-2 variants of concern and robust long-term memory B- and T-cell responses. With seroconversion rates as high as 98.3% in vaccinated individuals, BBV152 shows 77.8% and 93.4% protection from symptomatic COVID-19 disease and severe symptomatic COVID-19 disease respectively. Studies in pediatric populations show superior immunogenicity (geometric mean titer ratio of 1.76 compared to an adult) with a seroconversion rate of >95%. The reactogenicity and safety profiles were comparable across all pediatric age groups between 2-18 yrs. as in adults. Like most approved vaccines, the BBV152 booster given 6 months after full vaccination, reverses a waning immunity, restores the neutralization efficacy, and shows synergy in a heterologous prime-boost study with about 3-fold or 300% increase in neutralization titers against multiple SARS-CoV-2 variants of concern. Based on the interim Phase III data, BBV152 received full authorization for adults and emergency use authorization for children from ages 6 to 18 years in India. It is also licensed for emergency use in 14 countries globally. Over 313 million vaccine doses have already been administered in India alone by April 18th, 2022.

Riddle of Herd Immunity in SARS-CoV-2-Induced Viral Terrorism: Science to Society

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that presented in Wuhan, China in December of 2019. SARS-CoV-2-mediated coronavirus disease 2019 (COVID-19) is strongly associated with the rampant of infection with catastrophic morbidity. This pandemic has jiggled the society with its widespread social, psychologic, and economic distress. Society immunity or herd immunity is the most crucial and natural prophylactic vaccination interference against any infectious disease around the globe. It postulates protection at both the individual and population levels against pathogen-borne infections. The accomplishment of herd immunity is reliant upon the transmission efficiency of pathogens and the emerging natural immunity within a society. This is an exclusively pertinent mechanism to control any pandemic. The microbiome plays a crucial role in the coevolution of the body's immune cells, which are cardinal for bolstering a proficient vaccination process, ensuring herd immunity. The dynamics of interaction among microbiota, nutrients, and individual immunity determines the avidity of vaccines against several pathogens. Synchronization of microbial symbiosis preserves pathogen transmissibility and the engrossment of vaccination among different clusters based on the age and gender. Imbalance of nutrients refutes microbiome harmony, develops environmental enteropathy, and exacerbates immunity, which perturbs the efficacy of the vaccination process. Furthermore, discrepancies in the protective response of many vaccines in developing countries than developed countries are due to differences in healthy microbiota among the individuals in a particular cohort. We suggested that the rigorous pan-India oral poliovirus vaccination program for the past 30years has been finally capable of inducing herd immunity against poliovirus infection among societies, which may also inspire the commencement of natural heterologous immunity against SARS-CoV-2 infection. However, this anamnestic recall is somewhat counterintuitive, as antibody generation against original antigens of SARS-CoV-2 will be restrained due to original antigenic sin. © 2022 Elsevier Inc. All rights reserved.

mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits similar B cell expansion, neutralizing responses, and protection from Omicron.

SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-matched vaccines would enhance protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron. Neutralizing titers against D614G were 4,760 and 270 reciprocal ID50 at week 6 (peak) and week 41 (preboost), respectively, and 320 and 110 for Omicron. 2 weeks after the boost, titers against D614G and Omicron increased to 5,360 and 2,980 for mRNA-1273 boost and 2,670 and 1,930 for mRNA-Omicron, respectively. Similar increases against BA.2 were observed. Following either boost, 70%-80% of spike-specific B cells were cross-reactive against WA1 and Omicron. Equivalent control of virus replication in lower airways was observed following Omicron challenge 1 month after either boost. These data show that mRNA-1273 and mRNA-Omicron elicit comparable immunity and protection shortly after the boost.

Beta RBD boost broadens antibody-mediated protection against SARS-CoV-2 variants in animal models.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) with resistance to neutralizing antibodies are threatening to undermine vaccine efficacy. Vaccination and infection have led to widespread humoral immunity against the pandemic founder (Wu-Hu-1). Against this background, it is critical to assess the outcomes of subsequent immunization with variant antigens. It is not yet clear whether heterotypic boosts would be compromised by original antigenic sin, where pre-existing responses to a prior variant dampen responses to a new one, or whether the memory B cell repertoire would bridge the gap between Wu-Hu-1 and VOCs. We show, in macaques immunized with Wu-Hu-1 spike, that a single dose of adjuvanted beta variant receptor binding domain (RBD) protein broadens neutralizing antibody responses to heterologous VOCs. Passive transfer of plasma sampled after Wu-Hu-1 spike immunization only partially protects K18-hACE2 mice from lethal challenge with a beta variant isolate, whereas plasma sampled following heterotypic RBD boost protects completely against disease.

SARS-CoV-2 vaccination in the context of original antigenic sin.

Immunological memory is the ability of the adaptive immune system to ensure a persistent protective effect after immunization. However, it can also be a limitation to building a sufficient level of protective antibodies specific to new mutations of the virus. It is imperative to bear this phenomenon (called "original antigenic sin") in mind and make every effort to overcome its inherent pitfalls when updating current and designing new vaccines.

Is 'original antigenic sin' complicating indian vaccination drive against Covid-19?

India is in the grip of a devastating second wave of Covid-19. Many experts believe new variants of concern (VOC) are behind this unprecedented surge. Some media reports are hinting toward higher risk of Covid infection following Covid vaccinations. 'Original antigenic sin,' in which a prior exposure to an antigen leads to an ineffective response to a related antigen, may offer one immunological explanation for this unusual association. There is an urgent need of undertaking a detailed study to prove/disprove this association.

Dynamics of host immune responses to SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the most recent global health threat, is spreading throughout the world with worrisome speed, and the current wave of coronavirus disease 2019 (COVID-19) seems to have no mercy. While this mysterious virus challenges our ability to control viral infections, our opportunities to control the COVID-19 pandemic are gradually fading. Currently, pandemic management relies on preventive interventions. Although prevention is a good strategy to mitigate SARS-CoV-2 transmission, it still cannot be considered an absolute solution to eliminate this pandemic. Currently, developing a potent immunity against this viral infection seems to be the most promising strategy to drive down this ongoing global tragedy. However, with the emergence of new challenges in the context of immune responses to COVID-19, the road to control this devastating pandemic seems bumpier; thus, it is pivotal to characterize the dynamics of host immune responses to COVID-19, in order to develop efficient prophylactic and therapeutic tools. This begs the question of whether the effector mechanisms of the immune system are indeed potent or a possible contributing factor to developing more severe and lethal forms of COVID-19. In this review, the possible role of the immunopathologic phenomena including antibody-dependent enhancement, cytokine storm, and original antigenic sin in severity and mortality of COVID-19 will be discussed.

Original Antigenic Sin: the Downside of Immunological Memory and Implications for COVID-19.

The concept of original antigenic sin (OAS) was put forth many years ago to explain how humoral memory responses generated against one set of antigens can affect the nature of antibody responses elicited to challenge infections or vaccinations containing a similar but not identical array of antigens. Here, we highlight the link between OAS and the germinal center reaction (GCR), a process unique to activated B cells undergoing somatic hypermutation and class switch recombination. It is the powerful response of activated memory B cells and the accompanying GCR that establish the foundations of OAS. We apply these concepts to the current COVID-19 pandemic and put forth several possible scenarios whereby OAS may result in either beneficial or harmful outcomes depending, hypothetically, on prior exposure to antigens shared between SARS-CoV-2 and seasonal human coronaviruses (hCoVs) that include betacoronaviruses (e.g., HCoV-OC43 and HCoV-HKU1) and alphacoronaviruses (e.g., HCoV-NL63 and HCoV-HKU1) (E. M. Anderson, E. C. Goodwin, A. Verma, C. P. Arevalo, et al., medRxiv, 2020, https://doi.org/10.1101/2020.11.06.20227215; S. M. Kissler, C. Tedijanto, E. Goldstein, Y. H. Grad, and M. Lipsitch, Science 368:860-868, 2020, https://doi.org/10.1126/science.abb5793).

HLA, Immune Response, and Susceptibility to COVID-19.

The severe acute respiratory syndrome caused by Coronavirus 2 (SARS-CoV-2) that appeared in December 2019 has precipitated the global pandemic Coronavirus Disease 2019 (COVID-19). However, in many parts of Africa fewer than expected cases of COVID-19, with lower rates of mortality, have been reported. Individual human leukocyte antigen (HLA) alleles can affect both the susceptibility and the severity of viral infections. In the case of COVID-19 such an analysis may contribute to identifying individuals at higher risk of the disease and the epidemiological level to understanding the differences between countries in the epidemic patterns. It is also recognized that first antigen exposure influences the consequence of subsequent exposure. We thus propose a theory incorporating HLA antigens, the "original antigenic sin (OAS)" effect, and presentation of viral peptides which could explain with differential susceptibility or resistance to SARS-CoV-2 infections.

Humoral Responses and Serological Assays in SARS-CoV-2 Infections.

In December 2019, the novel betacoronavirus Severe Acute Respiratory Disease Coronavirus 2 (SARS-CoV-2) was first detected in Wuhan, China. SARS-CoV-2 has since become a pandemic virus resulting in hundreds of thousands of deaths and deep socioeconomic implications worldwide. In recent months, efforts have been directed towards detecting, tracking, and better understanding human humoral responses to SARS-CoV-2 infection. It has become critical to develop robust and reliable serological assays to characterize the abundance, neutralization efficiency, and duration of antibodies in virus-exposed individuals. Here we review the latest knowledge on humoral immune responses to SARS-CoV-2 infection, along with the benefits and limitations of currently available commercial and laboratory-based serological assays. We also highlight important serological considerations, such as antibody expression levels, stability and neutralization dynamics, as well as cross-reactivity and possible immunological back-boosting by seasonal coronaviruses. The ability to accurately detect, measure and characterize the various antibodies specific to SARS-CoV-2 is necessary for vaccine development, manage risk and exposure for healthcare and at-risk workers, and for monitoring reinfections with genetic variants and new strains of the virus. Having a thorough understanding of the benefits and cautions of standardized serological testing at a community level remains critically important in the design and implementation of future vaccination campaigns, epidemiological models of immunity, and public health measures that rely heavily on up-to-date knowledge of transmission dynamics.

A Novel Hypothesis for Original Antigenic Sin in the Severe Disease of SARS-CoV-2 Infection.

In this hypothesis, we address the biological/immunological pathway leading to severe disease or death after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying immune response is described with "original antigenic sin" (OAS) whereby previous infections influence the response to future virus encounters. We cite evidence for OAS-induced immunopathology in HIV-1 disease. We hypothesize that similar immune abnormalities can occur after infection with SARS-CoV-2. This hypothesis is supported by recent analysis of the antibodies in infected patients demonstrating serological and B cell abnormalities. The concept of symmetrical clonal regulation developed earlier for the immune network illustrates the pathway suggested by our hypothesis and may be helpful to develop strategies avoiding severe coronavirus disease 2019.