Background: 

Globally, variants of concern (VOC) have impacted the course of the COVID-19 pandemic. The pandemic has been highly dynamic, and as of September 2023, VOCs have been de-escalated but there are three variants of interest and seven under monitoring. Earlier in the pandemic, both the Delta and Omicron VOC were known for their higher transmissibility and potential for immune escape. Immunity against SARS-CoV-2 can result from infection or vaccination, or a combination of both, known as hybrid immunity. Individual immunity, in combination with other infections, prevention and control measures, is crucial in preventing reinfections and breakthrough cases. While vaccines have been developed successfully, ongoing monitoring of their effectiveness is essential due to the ever-evolving nature of the virus and the emergence of new variants. 

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McMaster University and the University of Ottawa have jointly conducted a living systematic review to assess the impact of VOCs on vaccine effectiveness in adults. This review has investigated various immunological outcomes from databases and grey literature searches from January 2020 to April 2023. Living evidence syntheses (LES) are valuable tools to continuously gather and consolidate evolving scientific evidence in rapidly changing fields like COVID-19 variants. The results will inform policymaking, research prioritization, and preparedness for future health crises. 

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Objectives: 

The goal of this living systematic review was to examine COVID-19 vaccine effectiveness against severe outcomes, transmission, and variants of concern of SARS-CoV-2. The results presented in the present summary relate to immunological outcomes. 

 

Methods: 

This living evidence synthesis is based on the framework of Crowcroft and Klein for research on vaccine effectiveness. This review follows Cochrane living systematic review guidance and Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions. The protocol has been registered on PROSPERO (CRD42022359790) and the Open Science Framework (https://osf.io/qacw4/). Any amendments to the protocol will be documented in the PROSPERO registration and the final published report. 

 

Results: 

Study characteristics: 

Total number of included studies: 212 included studies (out of a total of 8360 records obtained from database and grey literature searches published since January 2020). 

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Study designs: 48 randomized trials and 164 non-randomized studies. 

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Years of Publication: 2022 (77.46%), 2021 (9.38%), 2023 (3.76), and 20 preprints.  

 

Countries of study: 49 different countries, majority from China (15.95%), Thailand (9.39%), and the USA (9.39%). Only three of the included studies were conducted in Africa. 

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Participants: 

Sample population: Healthy volunteers, children, the general population, healthcare workers (HCW), nursing homes and homecare residents, and individuals with comorbidities at baseline.  

 

Age range: 5 to 88 years old. 

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Interventions: 

COVID-19 vaccines approved by, or under consideration in the World Health Organization's Emergency Use Listing/Prequalification (EUL/PQ) assessment process were considered.  

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Vaccines received by participants: Ad26.COV2.S, Ad5-nCoV, AstraZeneca, BBIBP-CorV, BBV152, BNT162b2, ChAdOx1,COVIran Barekat, Curevac, KCONVAC, mRNA-1273, mRNA-1273.211, mRNA-1273.214, mRNA-1273.222, MVC–COV1901, NVSI-06-08, NVX CoV2373, PHH-1V, RQ3013, SCTV01C, SpikoGen, Sputnik Light, Sputnik V, TURKOVAC, UB-612, VLA2001, WIBP-CorV, ZF2001 and ZR202-CoV.  

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Vaccine doses received: 1 to 5 doses. 

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Comparators: 

• Convalescent or unvaccinated individuals from the same or a similar setting.

 

• Relative effectiveness relating to booster doses, the comparator consists of a similar population who has received a fewer number of doses of the same vaccine.  

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• Relative effectiveness of different vaccine brands, the comparator consists of a similar population who has received a primary vaccine series and an equivalent number of booster doses. 

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Outcome assessed: 

We assessed the vaccine efficacy against SARS-CoV-2 variants of concern (VOC) by examining immunological indicators. These indicators encompassed parameters such as neutralization antibody activity, anti-SARS antibody titers, and cell-mediated immune response.  

 

VOCs: Only Delta (30.05% of studies), only Omicron (8.92% ), both Delta and Omicron (27.23%).Omicron subtypes include : Omicron BA.1, Omicron BA.1.1, Omicron BA.1.1.529, Omicron BA.2, Omicron BA.2.12.1, Omicron BA.2.13 ,Omicron BA.2.3, Omicron BA.2.75 ,Omicron BA.2.75.2, Omicron BA.3, Omicron BA.4.6, Omicron BA.4/5 and Omicron+R346K mutation. 

 

Immunological outcome measures: 

• Percentage distribution of Immunological outcome measures by included studies:

Neutralizing antibodies only (72.30%)
Neutralizing antibodies and Anti-SARS-CoV-2 antibodies (15.49%)
Neutralizing antibodies and Cell-mediated immunity (4.69%)
Neutralizing antibodies, Anti-SARS-CoV-2 antibodies, and Cell-mediated immunity (3.29%)
Cell-mediated immunity only (2.35%)
Anti-SARS-CoV-2 antibodies only (0.94%)
Anti-SARS-CoV-2 antibodies and Cell-mediated immunity (0.47%)

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• Neutralization antibodies activity measures: 

Neutralization antibodies reported: Anti spike, RBD and RBD-ACE2.  

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Neutralization assay techniques: Focus reduction assay, Cytopathic reduction assay, Live virus-based assay, Psuedotype virus assay, Surrogate virus assay, Plaque-based assay, and others (TCID50-based neutralization method, S-Fuse neutralization assay, Recombinant Ad26-neutralization assay, or neutralization assay not further-specified.  

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Neutralization antibody titre units: PRNT, NT, PVNT, PSVNA, IC, ID, FRNT, EC/ED, MNT, AU/ml, ND, and others such as LLOQ, RLU, TCID50, IU/ml, vMN, and qAC50.  

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Measures reported: GMT, mean and median.  

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• Anti-SARS antibody titer measurement: 

Anti-SARS antibodies reported: IgG, IgA, and IgM (Anti spike, RBD and Recombinant spike proteins). 

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Assay techniques: Chemiluminescence assays, Electro chemiluminescent assays, Enzyme-based assays, and others (Hemagglutination test, Surface plasmon resonance, S-Flow assay and TrimericS IgG quantitative immunoassay).  

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Anti-SARS antibody titre unit: BAU/mL, AU/mL, U/mL, AUC, EC50 and RU. 

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Measures reported: GMT, mean and median.  

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• Cell-mediated immune response measurement: 

Cell-mediated immune responses measured: T-cells response (CD4+Tcells and CD8+Tcells), B-cells response and Cytokines (IFN-y levels). 

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Assay techniques: Activation-induced marker (AIM) assay, ELISpot assay, Intracellular cytokine staining assay, TSPOT-Discovery test, and Flow Cytometry Analysis.  

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Measurement unit: SFU/million cells, SFC/million, and SFC/million PBMC.  

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Measures reported: GMT, mean and median.  

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Discussion, limitation, and conclusion: 

To our knowledge this is the first living systematic review on the effectiveness of SARS-CoV-2 on the Delta and Omicron VOCs. The study approach and process were appropriate for extracting a large volume of data. Study participants received anywhere from 1 to 5 doses of a COVID-19 vaccine and received varying amounts of the vaccine (both standard and fractional doses), had different time intervals between doses, or received a mixture of vaccines.  

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Additionally, we considered the infection status of vaccinated individuals, which included those with no prior infection and those with hybrid immunity (meaning they were infected before vaccination, experienced breakthrough infections, or were infected in-between vaccination doses), and the timing of sample collection after exposure (vaccination or infection) which ranged from 14 days to 1 year.  

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The analysis of the studies we included generated various comparison groups. These encompassed comparisons such as Booster vs Pre-boost, Vaccine-to-vaccine/Mix, Hybrid Immunity vs non-Hybrid Immunity, Dose Volume, Vaccinated vs Unvaccinated, Fractional vs Standard Dose, Age Group, Sex Group, and Dose Interval. 

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Further, the data we collected from the included studies presented a wide range of heterogeneity in the outcome measures and reporting. Studies varied widely in terms of what they measured related to immunological outcomes (e.g., types of antibodies reported), how they measured it (e.g., assays), and the standards they used. This diversity included the units of measurement, dilution percentages (e.g., 100, 90, 80, 50), as well as how the measurements were reported (GMT, median, and mean), and the specific cut-off points used to evaluate immune responses. 

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Because of these differences, it was challenging to conduct a meta-analysis analysis or comprehensive synthesis of the results to assess how effective SARS-CoV-2 is against the Delta and Omicron variants. As a result, we decided to present our findings separately from each study on an interactive dashboard known as the Nab VEVOC (Effectiveness of vaccine-induced neutralizing antibodies against variants of concern) dashboard. This study emphasizes the necessity for calibrating and standardizing assays to gain a comprehensive understanding of the absolute immunological response to the VOCs. 

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Authors: 

Gideon Darko Asamoah, gasamoah@uottawa.ca, Knowledge Synthesis and Application Unit, School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada 

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Nicole Shaver, nicole.shaver@uottawa.ca, Knowledge Synthesis and Application Unit, School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada. ORCID 0000-0003-3210-8895 

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Julian Little, jlittle@uottawa.ca, Knowledge Synthesis and Application Unit, School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada 

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Funding: 

This review is supported by a CIHR Operating grant (Funding reference number EG9 179477). Additional funding has been provided by Pillar 9 (Knowledge, Implementation and Training Team) of CoVaRR-Net. This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results. 

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How to cite: Asamoah GD., Shaver N., Little J (2023) Living Systematic Review on Immunological Outcomes of Vaccine Effectiveness on Variants of Concern Dashboard – The Nab VEVOC dashboard. https://www.ksau.ca/ve-voc-immunological-dashboard-1