scholarly journals Mechanistic modeling of SARS-CoV-2 immune memory, variants, and vaccines

2021 ◽  
Author(s):  
Jamie A Cohen ◽  
Robyn Margaret Stuart ◽  
Rafael C Nùñez ◽  
Katherine Rosenfeld ◽  
Bradley Wagner ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Severe Disease ◽  
Mechanistic Modeling ◽  
Joint Estimation ◽  
Immune Memory ◽  
Vaccination Programs ◽  
Epidemic Dynamics ◽  
Protection Against Infection ◽  
The Impact

Early waves of the SARS-CoV-2 pandemic were driven by importation events and subsequent policy responses. However, epidemic dynamics in 2021 are largely driven by the spread of more transmissible and/or immune-evading variants, which in turn are countered by vaccination programs. Here we describe updates to the methodology of Covasim (COVID-19 Agent-based Simulator) to account for immune trajectories over time, correlates of protection, co-circulation of different variants and the roll-out of multiple vaccines. We have extended recent work on neutralizing antibodies (NAbs) as a correlate of protection to account for protection against infection, symptomatic COVID-19, and severe disease using a joint estimation approach. We find that NAbs are strongly correlated with infection blocking and that natural infection provides stronger protection than vaccination for the same level of NAbs, though vaccines typically produce higher NAbs. We find only relatively weak correlations between NAbs and the probability of developing symptoms given a breakthrough infection, or the probability of severe disease given symptoms. A more refined understanding of breakthrough infections in individuals with natural and vaccine-derived immunity will have implications for timing of booster vaccines, the impact of emerging variants of concern on critical vaccination thresholds, and the need for ongoing non-pharmaceutical interventions.

scholarly journals Infection and Immune Memory: Variables in Robust Protection by Vaccines Against SARS-CoV-2

2021 ◽  
Vol 12 ◽  
Author(s):  
Pankaj Ahluwalia ◽  
Kumar Vaibhav ◽  
Meenakshi Ahluwalia ◽  
Ashis K. Mondal ◽  
Nikhil Sahajpal ◽  
...  
Keyword(s):  
Immune Response ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Severe Disease ◽  
Immunological Memory ◽  
Immune Memory ◽  
Erythroid Progenitor ◽  
Cd8 Cells ◽  
Future Design ◽  
Precise Knowledge

SARS-CoV-2 is the cause of a recent pandemic that has led to more than 3 million deaths worldwide. Most individuals are asymptomatic or display mild symptoms, which raises an inherent question as to how does the immune response differs from patients manifesting severe disease? During the initial phase of infection, dysregulated effector immune cells such as neutrophils, macrophages, monocytes, megakaryocytes, basophils, eosinophils, erythroid progenitor cells, and Th17 cells can alter the trajectory of an infected patient to severe disease. On the other hand, properly functioning CD4+, CD8+ cells, NK cells, and DCs reduce the disease severity. Detailed understanding of the immune response of convalescent individuals transitioning from the effector phase to the immunogenic memory phase can provide vital clues to understanding essential variables to assess vaccine-induced protection. Although neutralizing antibodies can wane over time, long-lasting B and T memory cells can persist in recovered individuals. The natural immunological memory captures the diverse repertoire of SARS-CoV-2 epitopes after natural infection whereas, currently approved vaccines are based on a single epitope, spike protein. It is essential to understand the nature of the immune response to natural infection to better identify ‘correlates of protection’ against this disease. This article discusses recent findings regarding immune response against natural infection to SARS-CoV-2 and the nature of immunogenic memory. More precise knowledge of the acute phase of immune response and its transition to immunological memory will contribute to the future design of vaccines and the identification of variables essential to maintain immune protection across diverse populations.

scholarly journals Third doses of COVID-19 vaccines reduce infection and transmission of SARS-CoV-2 and could prevent future surges in some populations

2021 ◽  
Author(s):  
Billy J Gardner ◽  
A. Marm Kilpatrick
Keyword(s):  
Vaccine Coverage ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Reproductive Number ◽  
Vaccine Protection ◽  
Contact Rates ◽  
Previous Infection ◽  
Antibody Titers ◽  
Protection Against Infection ◽  
The Impact

Background Vaccines have greatly reduced the impact of COVID-19 globally. Unfortunately, evidence indicates that immunity wanes following vaccination, especially with the Delta variant (B.1.617.2). Protection against severe disease and death remain high, but protection against milder disease and infection have dropped significantly. A third booster dose of two-dose vaccines has been approved in several countries to individuals at higher risk of severe disease to protect those individuals, but the benefit to boosting immunity in younger healthy individuals and the effects on transmission are less clear. Methods Here we use relationships between neutralizing antibody titers and vaccine protection against infection and transmission, combined with data on waning and boosting of neutralizing antibody titers to examine the impact of a third dose of the Pfizer vaccine on infection and transmission and its impact on the pathogen effective reproductive number Rt. Findings Eight months of waning reduced protection of the Pfizer vaccine against all infections from 80.0% (95% CI: 77% to 83%) to 60.4% (95% CI: 53% to 67%); a third dose (which increased neutralizing antibody titers 25.9- fold relative to levels after 8 months of waning) increased protection to 87.2% (95% CI: 83% to 91%). Increased protection against infection and transmission from third doses reduced Rt by 21% to 66% depending on vaccine coverage and previous infection and reduced Rt below 1 when vaccination coverage was high or contact rates were well below pre-pandemic levels. Interpretation A third dose of the Pfizer vaccine could reduce transmission of SARS-CoV-2, which would reduce infection in unvaccinated individuals and breakthrough infections in vaccinated individuals. While vaccination of unvaccinated individuals, especially in developing countries, would be more effective for reducing disease than providing a third dose to vaccinated individuals, the benefit of a third dose in reducing transmission is sizeable and increases with vaccine coverage and contact rates among individuals.

scholarly journals Comparative kinetics of SARS-CoV-2 anti-spike protein RBD IgGs and neutralizing antibodies in convalescent and naïve recipients of the BNT162b2 mRNA vaccine versus COVID-19 patients

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ioannis P. Trougakos ◽  
Evangelos Terpos ◽  
Christina Zirou ◽  
Aimilia D. Sklirou ◽  
Filia Apostolakou ◽  
...  
Keyword(s):  
Immune Response ◽  
Neutralizing Antibodies ◽  
Mononuclear Cells ◽  
Natural Infection ◽  
Severe Disease ◽  
Vaccination Campaign ◽  
Hospitalized Patients ◽  
Peripheral Blood Mononuclear ◽  
Post Vaccination ◽  
Antibody Titers

Abstract Background Coronavirus SARS-CoV-2, the causative agent of COVID-19, has caused a still evolving global pandemic. Given the worldwide vaccination campaign, the understanding of the vaccine-induced versus COVID-19-induced immunity will contribute to adjusting vaccine dosing strategies and speeding-up vaccination efforts. Methods Anti-spike-RBD IgGs and neutralizing antibodies (NAbs) titers were measured in BNT162b2 mRNA vaccinated participants (n = 250); we also investigated humoral and cellular immune responses in vaccinated individuals (n = 21) of this cohort 5 months post-vaccination and assayed NAbs levels in COVID-19 hospitalized patients (n = 60) with moderate or severe disease, as well as in COVID-19 recovered patients (n = 34). Results We found that one (boosting) dose of the BNT162b2 vaccine triggers robust immune (i.e., anti-spike-RBD IgGs and NAbs) responses in COVID-19 convalescent healthy recipients, while naïve recipients require both priming and boosting shots to acquire high antibody titers. Severe COVID-19 triggers an earlier and more intense (versus moderate disease) immune response in hospitalized patients; in all cases, however, antibody titers remain at high levels in COVID-19 recovered patients. Although virus infection promotes an earlier and more intense, versus priming vaccination, immune response, boosting vaccination induces antibody titers significantly higher and likely more durable versus COVID-19. In support, high anti-spike-RBD IgGs/NAbs titers along with spike (vaccine encoded antigen) specific T cell clones were found in the serum and peripheral blood mononuclear cells, respectively, of vaccinated individuals 5 months post-vaccination. Conclusions These findings support vaccination efficacy, also suggesting that vaccination likely offers more protection than natural infection. Graphical abstract

scholarly journals Detection of SARS-CoV-2 neutralizing antibodies with a cell-free PCR assay

2020 ◽  
Author(s):  
Kenneth Danh ◽  
Donna Grace Karp ◽  
Peter V Robinson ◽  
David Seftel ◽  
Mars Stone ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Severe Disease ◽  
Pcr Assay ◽  
Disease Symptoms ◽  
Dna Conjugates ◽  
A Cell ◽  
Pathogen Reduction ◽  
Development And Validation ◽  
The Impact ◽  
Level 2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to more than 4 million confirmed infections worldwide and over 300,000 deaths. While Remdesivir has recently received FDA emergency use authorization for treatment of SARS-CoV-2 infection, convalescent plasma (CP) with high titers of SARS-CoV-2 neutralizing antibodies (NAbs) from recovered donors remains a promising and widely accessible method to mitigate severe disease symptoms. Here, we describe the development and validation of a cell-free neutralization PCR assay using SARS-CoV-2 spike protein S1 and human ACE2 receptor-DNA conjugates. By comparing with samples collected prior to the outbreak, we confirmed that NAbs were specifically detected in COVID-19 cases. Using our unique assay, the NAb signals are detectable as early as 10 days after onset of symptoms and continue to rise, plateauing after 18 days. Notably, we showed that the use of licensed pathogen reduction technology to inactivate potentially contaminating infectious pathogens in CP did not alter NAb signals, paving a path to safely administer effective CP therapies. The described neutralization PCR assay can serve as a qualification tool to easily identify suitable CP donors of a potentially lifesaving therapy. In addition, this assay tool is readily deployable in standard laboratories with biosafety level 2 capability, and can yield results within 2-3 hr. This advancement can facilitate research on factors driving diverse COVID-19 disease manifestations, and to evaluate the impact of various CP processing protocols on CP therapeutic efficacy.

scholarly journals Modeling Dengue Immune Responses Mediatedby Antibodies: A Qualitative Study

Biology ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 941
Author(s):  
Afrina Andriani Sebayang ◽  
Hilda Fahlena ◽  
Vizda Anam ◽  
Damián Knopoff ◽  
Nico Stollenwerk ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Antibody Production ◽  
Natural Infection ◽  
Severe Disease ◽  
Dengue Infection ◽  
Immunological Response ◽  
Health Concern ◽  
Future Research ◽  
Model Framework ◽  
The Impact

Dengue fever is a viral mosquito-borne infection and a major international public health concern. With 2.5 billion people at risk of acquiring the infection around the world, disease severity is influenced by the immunological status of the individual, seronegative or seropositive, prior to natural infection. Caused by four antigenically related but distinct serotypes, DENV-1 to DENV-4, infection by one serotype confers life-long immunity to that serotype and a period of temporary cross-immunity (TCI) to other serotypes. The clinical response on exposure to a second serotype is complex with the so-called antibody-dependent enhancement (ADE) process, a disease augmentation phenomenon when pre-existing antibodies to previous dengue infection do not neutralize but rather enhance the new infection, used to explain the etiology of severe disease. In this paper, we present a minimalistic mathematical model framework developed to describe qualitatively the dengue immunological response mediated by antibodies. Three models are analyzed and compared: (i) primary dengue infection, (ii) secondary dengue infection with the same (homologous) dengue virus and (iii) secondary dengue infection with a different (heterologous) dengue virus. We explore the features of viral replication, antibody production and infection clearance over time. The model is developed based on body cells and free virus interactions resulting in infected cells activating antibody production. Our mathematical results are qualitatively similar to the ones described in the empiric immunology literature, providing insights into the immunopathogenesis of severe disease. Results presented here are of use for future research directions to evaluate the impact of dengue vaccines.

scholarly journals Antibody Response to the BNT162b2 mRNA COVID-19 Vaccine in Subjects with Prior SARS-CoV-2 Infection

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 422
Author(s):  
Federico Gobbi ◽  
Dora Buonfrate ◽  
Lucia Moro ◽  
Paola Rodari ◽  
Chiara Piubelli ◽  
...  
Keyword(s):  
Antibody Response ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Vaccine Dose ◽  
Neutralizing Antibody ◽  
Immune Memory ◽  
Effective Response ◽  
Infected People ◽  
Significant Difference ◽  
Antibody Titers

Although antibody levels progressively decrease following SARS-CoV-2 infection, the immune memory persists for months. Thus, individuals who naturally contracted SARS-CoV-2 are expected to develop a more rapid and sustained response to COVID-19 vaccines than naïve individuals. In this study, we analyzed the dynamics of the antibody response to the BNT162b2 mRNA COVID-19 vaccine in six healthcare workers who contracted SARS-CoV-2 in March 2020, in comparison to nine control subjects without a previous infection. The vaccine was well tolerated by both groups, with no significant difference in the frequency of vaccine-associated side effects, with the exception of local pain, which was more common in previously infected subjects. Overall, the titers of neutralizing antibodies were markedly higher in response to the vaccine than after natural infection. In all subjects with pre-existing immunity, a rapid increase in anti-spike receptor-binding domain (RBD) IgG antibodies and neutralizing antibody titers was observed one week after the first dose, which seemed to act as a booster. Notably, in previously infected individuals, neutralizing antibody titers 7 days after the first vaccine dose were not significantly different from those observed in naïve subjects 7 days after the second vaccine dose. These results suggest that, in previously infected people, a single dose of the vaccine might be sufficient to induce an effective response.

scholarly journals Effects of repeated vaccination and vaccine formulation on the induction of broadly neutralizing antibody responses against influenza A virus in children

2021 ◽  
Author(s):  
Sergey Yegorov ◽  
Daniel Celeste ◽  
Kimberly Braz Gomes ◽  
Jann C Ang ◽  
Colin Vandenhof ◽  
...  
Keyword(s):  
Influenza Vaccination ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Seasonal Influenza Vaccination ◽  
Vaccine Type ◽  
Paediatric Cohort ◽  
The Impact

The induction of broadly neutralizing antibodies (bNAbs) that target the hemagglutinin stalk domain is a promising strategy for the development of universal influenza virus vaccines. bNAbs can be boosted in adults by sequential exposure to heterosubtypic viruses through natural infection or vaccination. However, little is known about if/how bNAbs are induced by vaccination in more immunologically naive children. Here, we describe the impact of repeated seasonal influenza vaccination and vaccine type on induction of bNAbs in a well-characterized paediatric cohort enrolled in a series of randomized control trials of seasonal influenza vaccination. Repeated seasonal vaccination resulted in significant boosting of a durable bNAb response. Boosting of serological bNAbs titers was comparable within inactivated and live attenuated (LAIV) vaccinees and declined with age. These data provide new insights into vaccine-elicited bNAb induction in children, which has important implications for the design of universal influenza vaccine modalities in this critical population.

scholarly journals Herd immunity induced by COVID-19 vaccination programs to suppress epidemics caused by SARS-CoV-2 wild type and variants in China

2021 ◽  
Author(s):  
Hengcong Liu ◽  
Juanjuan Zhang ◽  
Jun Cai ◽  
Xiaowei Deng ◽  
Cheng Peng ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Disease Burden ◽  
Natural Infection ◽  
Severe Disease ◽  
Herd Immunity ◽  
Data Driven ◽  
Vaccination Program ◽  
Wild Type ◽  
Vaccination Programs ◽  
And Control

To allow a return to a pre-COVID-19 lifestyle, virtually every country has initiated a vaccination program to mitigate severe disease burden and control transmission; over 3.6 billion vaccine doses have been administered as of July 2021. However, it remains to be seen whether herd immunity will be within reach of these programs, especially as more transmissible SARS-CoV-2 variants continue to emerge. To address this question, we developed a data-driven model of SARS-CoV-2 transmission for Shanghai, China, a population with low prior immunity from natural infection. We found that extending the vaccination program to individuals aged 3-17 years plays a key role to reach herd immunity for the original SARS-CoV-2 lineages. With a vaccine efficacy 74% against infection, vaccine-induced herd immunity would require coverages of 93% or higher. Herd immunity for new variants, such as Alpha or Delta, can only be achieved with more efficacious vaccines and coverages above 80-90%. A continuation of the current pace of vaccination in China would reach 72% coverage by September 2021; although this program would fail to reach herd immunity it would reduce deaths by 95-100% in case of an outbreak. Efforts should be taken to increase population's confidence and willingness to be vaccinated and to guarantee highly efficacious vaccines against more transmissible variants of concern.

scholarly journals Longitudinal characterization of humoral and cellular immunity in hospitalized COVID-19 patients reveal immune persistence up to 9 months after infection

2021 ◽  
Author(s):  
John Tyler Sandberg ◽  
Renata Varnaitė ◽  
Wanda Christ ◽  
Puran Chen ◽  
Jagadeeswara R. Muvva ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cellular Immunity ◽  
Symptom Onset ◽  
Neutralizing Antibodies ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Immune Memory ◽  
Humoral And Cellular Immunity ◽  
Cell Responses

AbstractBackgroundInsights into early, specific humoral and cellular responses to infection with SARS-CoV-2, as well as the persistence and magnitude of resulting immune memory is important amidst the ongoing pandemic. The combination of humoral and cellular immunity will most likely contribute to protection from reinfection or severe disease.MethodsHere, we conducted a longitudinal study on hospitalized moderate and severe COVID-19 patients from the acute phase of disease into convalescence at five- and nine-months post symptom onset. Utilizing flow cytometry, serological assays as well as B cell and T cell FluoroSpot assays, we assessed the magnitude and specificity of humoral and cellular immune memory during and after human SARS-CoV-2 infection.FindingsDuring acute COVID-19, we observed an increase in germinal center activity, a substantial expansion of antibodysecreting cells, and the generation of SARS-CoV-2-neutralizing antibodies. Despite gradually decreasing antibody levels, we show persistent, neutralizing antibody titers as well as robust specific memory B cell responses and polyfunctional T cell responses at five- and nine-months after symptom onset in both moderate and severe COVID-19 patients. Long-term SARS-CoV-2 specific responses were marked by preferential targeting of spike over nucleocapsid protein.ConclusionsOur findings describe the initiation and, importantly, persistence of cellular and humoral SARS-CoV-2 specific immunological memory in hospitalized COVID-19 patients long after recovery, likely contributing towards protection against reinfection.

scholarly journals Modeling Dengue Immune Responses Mediated by Antibodies: a Qualitative Study

2021 ◽  
Author(s):  
Afrina Andriani Sebayang ◽  
Hilda Fahlena ◽  
Vizda Anam ◽  
Damián Knopoff ◽  
Nico Stollenwerk ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Antibody Production ◽  
Natural Infection ◽  
Severe Disease ◽  
Dengue Infection ◽  
Immunological Response ◽  
Health Concern ◽  
Future Research ◽  
Model Framework ◽  
The Impact

Dengue fever is a viral mosquito-borne infection, a major international public health concern. With 2.5 billion people at risk of acquiring the infection around the world, disease severity is influenced by the immunological status of the individual, seronegative or seropositive, prior to natural infection. Caused by four antigenically related but distinct serotypes, DENV-1 to DENV-4, infection by one serotype confers life-long immunity to that serotype and a period of temporary cross-immunity (TCI) to other serotypes. The clinical response on exposure to a second serotype is complex with the so-called Antibody-Dependent enhancement (ADE) process, a disease augmentation phenomenon when pre-existing antibodies to previous dengue infection do not neutralize but rather enhance the new infection, used to explain the etiology of severe disease. In this paper, we present a minimalistic mathematical model framework developed to describe qualitatively the dengue immunological response mediated by antibodies. Three models are analyzed and compared: i) primary dengue infection, ii) secondary dengue infection with the same (homologous) dengue virus and iii) secondary dengue infection with a different (heterologous) dengue virus. We explore the features of viral replication, antibody production, and infection clearance over time. The model is developed based on body cells and free virus interactions resulting in infected cells activating antibody production. Our mathematical results are qualitatively similar to the ones described in the empiric immunology literature, providing insights on the immunopathogenesis of severe disease. Results presented here are of use for future research directions to evaluate the impact of dengue vaccines.

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