Authors Angel Yun-Kuan Thye Loh Teng-Hern Tan Jodi Woan Fei Law Vengadesh Letchumanan DOI: https://doi.org/10.36877/pmmb.a0000256 Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that resulted in the COVID-19 global pandemic had consequently led to the development of different types of COVID-19 vaccines, including the messenger RNA (mRNA) vaccines, inactivated virus vaccines, a protein subunit vaccine, and viral vector recombinant vaccines. This review aims to discuss the various COVID-19 booster vaccines that are being authorized and administered, the eligibility criteria for the different booster vaccines, and the extent of protection these booster vaccines provide in the United States (US), Israel, United Kingdom (UK), Singapore and Chile.

We packaged SARS-CoV-2 pseudoviruses using the omicron spike and used them to enter HEK293T cells stably expressing human ACE2 [5 ]. As comparisons, we also packaged two other SARS-CoV-2 pseudoviruses using the spikes from a prototypic strain and delta strain, respectively. Sera from two groups of vaccinated people were collected: (i) ten people who had received two doses of the Pfizer mRNA spike vaccine; (ii) ten people who had received three doses of the same vaccine.

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Heterologous boosting Author(s) Country N enrolled Schedules (n ), heterologous boost Schedules (n ), homologous boost Study design Age range (in years) Randomization Outcome measures Key findings Atmar et al ., 2021 69 USA 458 JAN + MOD (53) JAN + BNT (53) 2 x MOD + JAN (49) 2 x MOD + BNT (51) 2 x BNT + JAN (51) 2 x BNT + MOD (50) JAN + JAN (50) 2 x MOD + MOD (51) 2 x BNT + BNT (50) Non-randomized CT (Mix-and- match study) 19–85 No Safety, reactogenicity, and humoral immunogenicity on 15 and 29 days Reactogenicity similar to primary series; no vaccine-related SAEs Homologous and heterologous boosters were well-tolerated and immunogenic in adults Yorsaeng et al ., 2021 70 Thailand 549 2 x SINOVAC + AZ (n = 210) N/A Observational study 40–48 No SARS-CoV-2 spike receptor-binding-domain (RBD) IgG, anti-RBD total Ig and antispike protein 1 (S1) IgA High immunogenicity of AZD1222 booster after completion of two-dose inactivated vaccines Li et al ., 2021 71 China 300 2 x SINOVAC + CANSINO (95 PP) 1 x SINOVAC + CANSINO (49 PP) 2 x SINOVAC + SINOVAC (100 PP) 1 x SINOVAC + SINOVAC (49 PP) Observer-blind RCT 18–59 Yes Neutralizing antibodies against live SARS-CoV-2 at 14 and 28 days after the booster dose No SAEs; heterologous boost associated with more frequent AEs (particularly injection-site pain), but generally mild/moderate Keskin et al ., 2021 72 Turkey 69 HCWs 2 x SINOVAC + BNT (27) 2 x SINOVAC + SINOVAC (18) Observational study 41 ± 10.9 Yes To investigate the interplay between humoral immune responses IgG-N titres for both groups showed statistically significant differences (both p-values 55y: AZ/BNT, unclear interval (n = 22) ≤55y: BNT/BNT, unclear interval (n = 33) > 55y: AZ/AZ, unclear interval (n = 22) > 55y: BNT/BNT, unclear interval (n = 22) Prospective cohort of seronegative HCWs 20–75 No Determination of neutralizing antibodies using a live virus-based assay Stronger antibody response elected with ChAdOx1-S/BNT162b2 heterologous regimen among HCWs older than 55 years than either of the homologous regimens. Heterologous boosting Author(s) Country N enrolled Schedules (n ), heterologous boost Schedules (n ), homologous boost Study design Age range (in years) Randomization Outcome measures Key findings Atmar et al ., 2021 69 USA 458 JAN + MOD (53) JAN + BNT (53) 2 x MOD + JAN (49) 2 x MOD + BNT (51) 2 x BNT + JAN (51) 2 x BNT + MOD (50) JAN + JAN (50) 2 x MOD + MOD (51) 2 x BNT + BNT (50) Non-randomized CT (Mix-and- match study) 19–85 No Safety, reactogenicity, and humoral immunogenicity on 15 and 29 days Reactogenicity similar to primary series; no vaccine-related SAEs Homologous and heterologous boosters were well-tolerated and immunogenic in adults Yorsaeng et al ., 2021 70 Thailand 549 2 x SINOVAC + AZ (n = 210) N/A Observational study 40–48 No SARS-CoV-2 spike receptor-binding-domain (RBD) IgG, anti-RBD total Ig and antispike protein 1 (S1) IgA High immunogenicity of AZD1222 booster after completion of two-dose inactivated vaccines Li et al ., 2021 71 China 300 2 x SINOVAC + CANSINO (95 PP) 1 x SINOVAC + CANSINO (49 PP) 2 x SINOVAC + SINOVAC (100 PP) 1 x SINOVAC + SINOVAC (49 PP) Observer-blind RCT 18–59 Yes Neutralizing antibodies against live SARS-CoV-2 at 14 and 28 days after the booster dose No SAEs; heterologous boost associated with more frequent AEs (particularly injection-site pain), but generally mild/moderate Keskin et al ., 2021 72 Turkey 69 HCWs 2 x SINOVAC + BNT (27) 2 x SINOVAC + SINOVAC (18) Observational study 41 ± 10.9 Yes To investigate the interplay between humoral immune responses IgG-N titres for both groups showed statistically significant differences (both p-values 55y: AZ/BNT, unclear interval (n = 22) ≤55y: BNT/BNT, unclear interval (n = 33) > 55y: AZ/AZ, unclear interval (n = 22) > 55y: BNT/BNT, unclear interval (n = 22) Prospective cohort of seronegative HCWs 20–75 No Determination of neutralizing antibodies using a live virus-based assay Stronger antibody response elected with ChAdOx1-S/BNT162b2 heterologous regimen among HCWs older than 55 years than either of the homologous regimens.

This was followed by the AstraZeneca/Oxford COVID-19 vaccine, manufactured by the Serum Institute of India and SKBio on 15 February 2021, and most recently, on 12 March 2021, the Ad26.COV2.S, developed by Janssen (Johnson & Johnson) and Moderna on 30 April. 4 COVAX, coordinated by WHO, Gavi: The Vaccine Alliance, the Coalition for Epidemic Preparedness Innovations (CEPI), acts as a programme that supports the development of COVID-19 vaccine candidates and negotiates their pricing to ensure low-and-middle-income countries have a fair shot at receiving vaccines. 5 This article aims at discussing the most recent WHO-approved COVID-19 vaccine subtypes, their status and geographical scheduled updates as of 4 May 2021. The Oxford/AstraZeneca was able to overcome this disadvantage by using the Chimpanzee adenovirus (ChAdOx1) which represents an alternative to the human Ad vector and lacks preexisting immunity in humans. 16 17 Table 1 Upcoming vaccines in phase III trials as of 4 May 2021 36 table 1 Name Platform Countries that are producing it WHO status Anticipated release date Sinovac Inactivated, produced in Vero cells China In progress Early May Sinopharm Inactivated, produced in Vero cells Beijing In progress Early May Name Platform Countries that are producing it WHO status Anticipated release date Sinovac Inactivated, produced in Vero cells China In progress Early May Sinopharm Inactivated, produced in Vero cells Beijing In progress Early May Table 1 Upcoming vaccines in phase III trials as of 4 May 2021 36 table 1 Name Platform Countries that are producing it WHO status Anticipated release date Sinovac Inactivated, produced in Vero cells China In progress Early May Sinopharm Inactivated, produced in Vero cells Beijing In progress Early May Name Platform Countries that are producing it WHO status Anticipated release date Sinovac Inactivated, produced in Vero cells China In progress Early May Sinopharm Inactivated, produced in Vero cells Beijing In progress Early May Trials and limitations Pfizer vaccine/BNT162b2 Trial A randomised controlled trial was designed to evaluate the efficacy of the Pfizer vaccine which consisted of a group of participants aged 16 and over.

Individuals were offered either a full dose of the BNT162b2 (Comirnaty, Pfizer-BioNTech) vaccine or a half dose of the mRNA-1273 (Spikevax, Moderna) vaccine, irrespective of the vaccine received as the primary course Methods We used a test-negative case-control design to estimate the Vaccine Effectiveness (VE) of the booster dose BNT162b2 (Comirnaty, Pfizer-BioNTech) in those aged over 50 against symptomatic disease in post booster time intervals compared to individuals at least 140 days post a second dose with no booster dose recorded. Results The relative VE estimate in the 14 days after the BNT162b2 (Comirnaty, Pfizer-BioNTech) booster dose, compared to individuals that received a two-dose primary course, was 87.4 (95% confidence interval 84.9-89.4) in those individuals who received two doses ChAdOx1-S (Vaxzevria, AstraZeneca) as a primary course and 84.4 (95% confidence interval 82.8-85.8) in those individuals who received two doses of BNT162b2 (Comirnaty, Pfizer-BioNTech) as a primary course.

Thompson , PhD, 1 and Bruce Fireman 8 CDC recommends that all persons aged ≥12 years receive a booster dose of COVID-19 mRNA vaccine ≥5 months after completion of a primary mRNA vaccination series and that immunocompromised persons receive a third primary dose.* Waning of vaccine protection after 2 doses of mRNA vaccine has been observed during the period of the SARS-CoV-2 B.1.617.2 (Delta) variant predominance† (1 –5 ), but little is known about durability of protection after 3 doses during periods of Delta or SARS-CoV-2 B.1.1.529 (Omicron) variant predominance. A test-negative case-control study design using data from eight VISION Network sites§ examined vaccine effectiveness (VE) against COVID-19 emergency department/urgent care (ED/UC) visits and hospitalizations among U.S. adults aged ≥18 years at various time points after receipt of a second or third vaccine dose during two periods: Delta variant predominance and Omicron variant predominance (i.e., periods when each variant accounted for ≥50% of sequenced isolates).¶ Persons categorized as having received 3 doses included those who received a third dose in a primary series or a booster dose after a 2 dose primary series (including the reduced-dosage Moderna booster). The VISION Network analyzed 241,204 ED/UC encounters** and 93,408 hospitalizations across 10 states during August 26, 2021–January 22, 2022.

Here we present available data on effectiveness of boosters, including against Omicron, and how this relates to the Asia-Pacific region. Early data from the UK suggests Pfizer/BioNTech boosters may enhance effectiveness against infection with Omicron from around 35% from 15 weeks after the second dose to over 70% (data not peer-reviewed). In Denmark, boosters increased effectiveness against infection with Omicron from

Details: Alternative Title: MMWR Morb Mortal Wkly Rep Description: Four COVID-19 vaccines are currently approved for primary series vaccination in the United States under a Biologics License Application or authorized under an emergency use authorization (EUA) by the Food and Drug Administration (FDA), and recommended for primary series vaccination by the Advisory Committee on Immunization Practices (ACIP): 1) the 2- or 3-dose monovalent mRNA BNT162b2 (Pfizer-BioNTech, Comirnaty) COVID-19 vaccine; 2) the 2- or 3-dose monovalent mRNA mRNA-1273 (Moderna, Spikevax) COVID-19 vaccine; 3) the single-dose adenovirus vector-based Ad26.COV.S (Janssen [Johnson & Johnson]) COVID-19 vaccine; and 4) the 2-dose adjuvanted, protein subunit-based NVX-CoV2373 (Novavax) COVID-19 vaccine. The number of doses recommended is based on recipient age and immunocompromise status (1). For additional protection, FDA has amended EUAs to allow for COVID-19 booster doses in eligible persons (1). Because COVID-19 vaccines have demonstrated decreased effectiveness during the period when the Omicron variant (B.1.1.529) of SARS-CoV-2 predominated, bivalent booster doses (i.e., vaccine with equal components from the ancestral and Omicron strains) were considered for the express purpose of improving protection conferred by COVID-19 vaccine booster doses (2). During September-October 2022, FDA authorized bivalent mRNA vaccines for use as a booster dose in persons aged ≥5 years who completed any FDA-approved or FDA-authorized primary series and removed EUAs for monovalent COVID-19 booster doses (1). Pfizer-BioNTech and Moderna bivalent booster vaccines each contain equal amounts of spike mRNA from the ancestral and Omicron BA.4/BA.5 strains.

A description of the eligible tests is given in Supplementary Table 1 . Vaccine effectiveness for symptomatic disease An overall effect on the proportion of cases and controls was seen from around day 7 after the booster dose and stabilized at day 11 (Extended Data Fig. 1 ). In individuals aged 18 to 49 years where the primary course was ChAdOx1-S vaccine, relative to those who had received only two doses, effectiveness against symptomatic disease peaked at 14–35 days after the BNT162b2 booster at 89.6% (95% CI, 88.6–90.4) and 95.3% (95% CI, 91.8–97.3) after the mRNA-1273 booster (Table 2 and Fig. 1 ). In individuals where BNT162b2 was the primary course, relative vaccine effectiveness 14-34 days a BNT162b2 booster was 82.8% (81.8-83.7) and after a mRNA-1273 booster 90.9% (84.5–94.7). Relative vaccine effectiveness with the BNT162b2 booster decreased slightly in the 35- to 69-day and ≥70-day periods (later follow-up was not available for mRNA-1273). The same analysis in individuals aged 50 years and older gave similar results (Table 2 and Fig. 1 ). Table 2 Vaccine effectiveness against symptomatic disease for the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) booster vaccines in England by age group Full size table Fig. 1: Estimates of vaccine effectiveness against symptomatic disease after booster according to primary course. a ,b , Vaccine effectiveness estimates (95% CI) against symptomatic disease in time intervals after booster according to primary course in individuals aged 18–49 years (a ) 50 years and older (b ). Dose 2 was received at 175 days as the baseline. Full size image Vaccine effectiveness against death in individuals 50 years and older 14–34 days after a BNT162b2 booster dose relative to the unvaccinated was 97.8 (95% CI, 94.4–99.1) after a ChAdOx1-S primary course and 98.7% (95% CI, 97.4–99.4) when the primary course was BNT162b2 (Table 4 and Fig. 2 ) Table 4 Vaccine effectiveness against death for the BNT162b2 (Pfizer-BioNTech) booster vaccine in England in individuals aged 50 years and older Full size table Interval between dose 2 and the booster dose After assessing the distribution of intervals between dose 2 and the booster dose for cases and controls by age group and manufacturer, the interval between dose 2 and the booster was split into three periods: 25–29, 30–34 and 35 or more weeks (Extended Data Fig. 4 ). Due to the roll out of the vaccine program, there were more individuals who had received a second dose of BNT162b2 at an earlier time point; therefore, the majority of the individuals who had the longest interval between dose 2 and the booster had a BNT162b2 primary course.