Effectiveness of mRNA, protein subunit vaccine and viral vectors vaccines against SARS-CoV-2 in people over 18 years old: a systematic review

Figures & data

Table 1. Characteristics of included studies.

Ref.	Country	Population, setting	Inter details	Investigated outcomes	Study aims	Main Results
[11]	USA	A total of 30,420 participants of 18 years old or older with no known history of SARS-CoV-2 infection and with locations or circumstances that put them at an appreciable risk of SARS- CoV-2 infection, a high risk of severe COVID-19, or both.	Participants were randomly assigned in a 1:1 ratio, using a centralized interactive response technology system, to receive vaccine or placebo. Assignment was stratified, based on age and COVID-19 complications risk criteria, into the following risk groups: persons 65 years of age or older, persons younger than 65 years of age who were at heightened risk (at risk) for severe COVID-19, and persons younger than 65 years of age without heightened risk (not at risk).	Clinical trial, safety assessments and efficacy assessments.	To report the primary analysis results of the COVE phase 3 trial.	Clinical trial: SARS-CoV-2 infection at baseline was present in 2.3% of participants in the mRNA- 1273 group and in 2.2% in the placebo group. Safety assessments: In the mRNA-1273 group, injection-site events were mostly grades 1 or 2 and lasted 2.6 and 3.2 days, respectively, after the first and second doses. Pain following injection was the most prevalent injection-site occurrence. The severity of the solicited systemic events increased after the second dose in the mRNA-1273 group, with an increase in proportions of grade 2 events (from 16.5% after the first dose to 38.1% after the second dose) and grade 3 events (from 2.9% to 15.8%). Efficacy assessments: 11 cases in the vaccine group (3.3 per 1000 person-years; 95% CI 1.7 to 6.0) were diagnosed with COVID-19, indicating 94.1% efficacy of the mRNA-1273 vaccine (95% CI 89.3 to 96.8%; P < 0.001) for the prevention of symptomatic SARS-CoV-2 infection.
[35]	GR	A total of 425 Greek healthcare workers, 63 of whom were previously infected convalescent subjects with PCR-confirmed SARS-CoV-2 infection one to 4.5 months prior to vaccination with the Pfizer-BioNTech COVID-19 BNT162b2 vaccine.	SARS-CoV-2 IgG II Quant assay was employed on serum samples to monitor titers of neutralizing IgGs against the RBD of the S1 subunit of the spike protein of SARS-CoV-2.	IgG levels and antibody titers.	To enhance insight into the humoral immunity and neutralizing antibody generation elicited 14 days post-immunization with the first dose of BNT162b2- mRNA COVID-19 vaccine in real-world settings.	IgG levels: 392 participants received a positive outcome in the IgG assay conducted 14 days after the first dose (92.2%; 95% CI 590.70–836.39). In fact, GMC of Anti SARS-CoV-2 Spike IgG antibodies 14 days post-immunization with the first dose of the BNT162b2 vaccine were 1780.73 AU/mL (20- years old), 1552.00 AU/mL (30- years old), 674.35 AU/mL (40- years old), 357.70 AU/mL (50- years old), and 155.80 AU/mL (60- years old). Antibody titers: antibody titers did not significantly differ among participants aged 20–49 years, but a significant decline was marked in the age group of 50–59 years, which was further accentuated in subjects aged over 60.
[36]	BR, ZA, and UK	A total of 11,636 participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline).	The model contained terms for study, treatment group, and age group (18–55, 56–69, and ≥70 years) at randomization. Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 10^10 viral particles (SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort).		To evaluate the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials.	Safety assessments: Serious side effects were experienced by 168 subjects, 79 of whom were vaccinated with ChAdOx1 nCoV-19. A total of 84 events occurred in the ChAdOx1 nCoV-19 group. Approximately 14 days after receiving the ChAdOx1 nCoV-19 booster shot, a case of transverse myelitis was reported. Efficacy assessments: Participants who received two SD vaccines, vaccine efficacy was 62.1% (95% CI 41.0 to 75.7), whereas in those who received a LD as their first dose of vaccine, efficacy was higher at 90.0% (67.4–97.0). Vaccination effectiveness in the SD/SD cohort aged 18–55 years was 60.3% (95% CI 25.1 to 77.9; p = 0.019). When the SD/SD analysis was narrowed down to individuals who had their immunizations more than 8 weeks apart, vaccine effectiveness was 65.6% (24.5 to 84.4; p = 0.082).
[15]	USA	A total of 45 healthy adults between 18 to 55 years of age who received two injections of mRNA-1273 vaccine 28 days apart at a dose of 25 μg, 100 μg, or 250 μg.	The vaccine was administered as a 0.5-ml injection in the deltoid muscle on days 1 and 29; follow-up visits were scheduled for 7 and 14 days after each vaccination and on days 57, 119, 209, and 394.	Assessment of SARS-CoV-2 binding antibody and neutralizing responses and assessment of SARS-CoV-2 T-cell responses.	To conduct a first-in-human phase 1 clinical trial in healthy adults to evaluate the safety and immunogenicity of mRNA-1273.	Safety assessments: No serious adverse events were noted. After the first vaccination, solicited systemic adverse events were reported in 33% of participants in the 25-μg group, 67% in the 100-μg group, and 53% in the 250-μg group; all were mild or moderate in severity. Solicited systemic adverse events were more common after the second vaccination and occurred in 54% of participants in the 25-μg group, 100% in the 100-μg group and 250-μg group. Assessment of SARS-CoV-2 binding antibody and neutralizing responses: GMTs to S-2P increased rapidly after the first vaccination, with seroconversion in all participants by day 15. No participant had detectable PsVNA responses before vaccination. After the first vaccination, PsVNA responses were detected in <50% of the participants. However, after the second vaccination, PsVNA responses were identified in all participants. Higher responses were found with higher doses. Assessment of SARS-CoV-2 T-cell responses: The 25-μg and 100-μg doses elicited CD4 T-cell responses to S-2P were strongly biased toward expression of Th1 cytokines (TNF-α > IL-2 > IFN-γ). CD8 T-cell responses to S-2P were detected at low levels after the second vaccination in the 100-μg dose group.
[37]	USA	A total of 195 healthy adults between 18 to 55 years of age or 65 to 85 years of age were eligible.	Groups of participants 18 to 55 years of age and 65 to 85 years of age were to receive doses of 10 μg, 20 μg, or 30 μg of BNT162b1, BNT162b2 or placebo on a two-dose schedule; one group of participants 18 to 55 years of age was assigned to receive 100-μg doses of BNT162b1 or placebo.	Safety and immunogenicity assessments.	To report the full set of safety and immunogenicity data from the phase 1 portion of an ongoing randomized, placebo-controlled, observer- blinded, dose-escalation trial in the US that was used to select the final vaccine candidate, as well as the comparison of the safety and immunogenicity of both vaccine candidates and additional phase 1 data that have been collected since candidate selection.	Safety assessments: Participants 18 to 55 years of age who received 10 μg, 20 μg, or 30 μg of BNT162b1 reported mild-to-moderate local reactions. Similar pattern was observed after vaccination with BNT162b2. Participants 18 to 55 years of age who received 10 μg, 20 μg, or 30 μg of BNT162b1 had mild-to-moderate fever and chills. Systemic events in response to BNT162b2 were milder than those in response to BNT162b1. Immunogenicity assessments: Antigen-binding IgG and virus-neutralizing responses to vaccination with 10 μg to 30 μg of BNT162b1 or BNT162b2 were boosted by the second dose in both the younger and the older adults. Both vaccines elicited generally lower antigen-binding IgG and virus-neutralizing responses in participants 65 to 85 years of age than in those 18 to 55 years of age. Higher doses appeared to elicit somewhat higher antibody responses.
[38]	CN	A total of 50 healthy adults aged 18–59 years, without a history of SARS-CoV or SARS-CoV-2 infection, an RT-PCR-positive test result for SARS-CoV-2, a history of contact with confirmed or suspected COVID-19 cases, and severe allergies to any component of the vaccine were eligible for enrollment.	Participants in phase 1 were randomly assigned (2:2:1) into three groups to receive three doses of the vaccine (25 μg or 50 μg dose) or placebo on day 0, 30, and 60. Participants in phase 2 were randomly assigned (1:1:1:1:1:1) into six groups, with three groups receiving two doses of the vaccine (25 μg or 50 μg dose) or placebo, 30 days apart, and three groups receiving three doses of the vaccine (25 μg or 50 μg dose) or placebo, 30 days apart.		To assess the safety and immunogenicity of this vaccine, ZF2001, and determine the appropriate dose and schedule for an efficacy study.	Safety assessments: In the phase 1 trial, 60% of participants in the placebo group, 70% in the 25 μg group, and 90% of in the 50 μg group reported at least one adverse event within 30 days after vaccination. No significant differences between-group were found. A total of 10% grade 3 or worse adverse events were reported in the 50 μg group were found. In the phase 2 trial, the overall frequency of adverse events was low within 30 days after vaccination. Among participants receiving two doses, 25% in the placebo group, 29% in the 25 μg group, and 33% in the 50 μg group reported at least one adverse event. Immunogenicity assessments: Phase 1 trial: GMTs of vaccine-induced RBD-binding IgG were 23.1 in the 25 μg dose group and 40.8 in the 50 μg dose group and increased to 1077.0 in the 25 μg dose group and 825.5 in the 50 μg dose group at day 30 after the second dose. GMTs further increased to 2719.5 in the 25 μg group and 2776.8 in the 50 μg group at day 30 after the third dose. The SARS-CoV-2-neutralizing GMTs were 14.0 (95% CI 8.0–24.6) in the 25 μg group and 11.4 (6.6–19.8) in the 50 μg group at day 30 after the second dose and increased to 94.5 (49.3–181.3) in the 25 μg group and 117.8 (64.6–214.9) in the 50 μg group at day 7 after the third dose. Phase 2 trial: Neutralizing GMTs against live SARS-CoV-2 14 days after the second dose in participants on the two-dose schedule were 17.7 (95% CI 13.6–23.1) in the 25 μg group and 14.1 (95% CI 10.8–18.3) in the 50 μg group. No increase in T-cell cytokines was observed in the placebo group. By contrast, the 25 μg and 50 μg doses elicited moderate levels of both Th1 (IFNγ and IL-2) and Th2 (IL-4 and IL-5) cytokine production after the immunizations.
[39]	USA, CL, and PE	A total of 34,117 people over 18 years old were screened. A total of 32,451 met the eligibility standards and were randomized to receive the AZD1222 vaccine or a placebo.	Participants were administered two intramuscular injections of AZD1222 (5 × 10^10 virus particles) or saline placebo on days 1 and 29 (−3 to +7 days). The randomization was stratified by age (18 to 64 years and 65 years or older), with the aim of reaching 25% of individuals 65 years of age or older. All individuals who were SARS-CoV-2 seronegative at baseline, who got two doses of vaccination or placebo, and who stayed in the study for 15 days or more after their second dose were included in the analysis.	Safety, efficacy, and immunogenicity.	To evaluate the immunogenicity, safety, and efficacy of AZD1222 in protecting healthy adults at high risk of SARS-CoV-2 infection, including high risk of symptomatic and severe COVID-19.	Safety assessments: In total, 8771 subjects in the AZD1222 group and 3201 subjects in the placebo group reported side effects. The most prevalent adverse effects were general pain (8.2% in the AZD1222 group and 2.3% in the placebo group), headache (6.2% and 4.6%, respectively), injection-site discomfort (6.8% and 2.0%), and tiredness (5.1% and 3.5%). The AZD1222 group had 101 participants (0.5%) with 119 significant adverse events, while the placebo group had 53 participants (0.5%) with 59 incidents. Efficacy assessments: The AZD1222 vaccination effectiveness was estimated to be 74.0% (95% CI; 65.3 to 80.5; P < 0.001). The efficacy of the vaccine was like the patients who got their second dose at a prolonged dosing interval (78.1%; 95% CI; 49.2 to 90.6). Immunogenicity assessments: Seronegative participants who received AZD1222 showed significant vaccine-induced serum IgG responses to the spike protein. Neutralizing antibody levels were higher than baseline in the AZD1222 group throughout the experiment and continued to rise after a second dose, but they remained low in the placebo group.
[40]	UK	A total of 560 participants over the age of 18 received either a MenACWY (control) vaccination or an intramuscular ChAdOx1 nCoV-19 (2.2 × 10^10 virus particles) shot. The prime-booster treatments were separated by 28 days. Following that, individuals for the SD group (3.5–6.5 × 10^10 ChAdOx1 nCoV-19 virus particles) were chosen using the same randomization methods.	A LD of 2.2 × 10^10 virus particles and a SD of 3.5–6.5 × 10^10 virus particles were administered to people of various ages. ChAdOx1 nCoV-19 was given as a single dose or in two doses (28 days apart) at a LD (2.2 × 10^10 virus particles) or a SD (3.5–6.5 × 10^10 virus particles).	Safety, reactogenicity, and immunogenicity profiles of ChAdOx1 nCoV-19 in adults (aged 56–69 years and ≥70 years).	To evaluate the safety, humoral and cellular immunogenicity of ChAdOx1 nCoV-19 vaccine after a single-dose and two-dose regimen in individuals over the age of 55.	Safety assessments: After the initial vaccination with SD ChAdOx1 nCoV-19, 88% of individuals aged 18–55, 73% of those aged 56–69, and 61% of those aged 70 and above experienced at least one local symptom. Similar proportions of local symptoms were reported following the boost vaccination with the SD of ChAdOx1 nCoV-19, with 76% of individuals aged 18–55, 72% of those aged 56–69, and 55% of those aged 70 and older experiencing at least one local symptom. After the initial vaccination with the SD of ChAdOx1 nCoV-19, 86% of individuals aged 18–55, 77% of those aged 56–69, and 65% of those aged 70 and above had at least one systemic symptom. Following the boost vaccination, the severity of symptoms reported in the SD groups decreased, with just 1% of individuals having a severe response, compared to 5% of people after the prime immunization. After receiving a regular dose of the ChAdOx1 nCoV-19 booster vaccination, 65% of individuals aged 18–55, 72% of those aged 56–69, and 43% of those aged 70 and above had at least one systemic adverse event. The incidence of objectively measured fever was low in the 18–55-year-old SD group (24%), and no fevers were observed in the 56–69-year-old or 70–and-older SD groups within 7 days following the main immunization with ChAdOx1 nCoV-19.
						Humoral and cellular immunogenicity assessments: Participants who received a SD ChAdOx1 nCoV-19 prime vaccination showed identical anti-spike antibody titers on day 28 as those who got a LD. At day 28, anti-spike IgG responses at all dose levels and across all dose groups decreased with advancing age LD groups: 18–55 years, 6439 AU/mL [IQR 4338–10,640]; 56–69 years, 4553 AU/mL [2657–12 462]; ≥70 years, 3565 AU/mL [1507–6345]; p = 0.003; SD groups: 18–55 years, 9807 AU/mL [IQR 5847–17,220]; 56–69 years, 5496 AU/mL [2548–12,061]; ≥70 years, 4156 [2122–12 595]; p = 0.004). At day 42, there were no significant differences in normalized titers between age groups (LD groups: 18–55 years, 161 [IQR 99–233], n = 41; 56–69 years, 143 [IQR 79–220], n = 28; ≥70 years, 150 [IQR 103–255], n = 34; p = 0.90; SD groups: 18–55 years, 193 [IQR IQR 113–238], n = 39; 56–69 years, 144 [IQR 119–347], n = 20; and ≥70 years, 161 [IQR 73–323], n = 47; p = 0.40).
[32,41]	USA	A total of 76 participants were screened, and 45 were randomized and vaccinated. The study population consisted of healthy male and female participants with a mean age of 35.4 years (range, 19–54 years); 51.1% were male and 48.9% were female. Most participants self-reported as white (82.2%) and non-Hispanic/non-Latin (93.3%).	Participants were randomized as follows: 12 participants were vaccinated with 10 μg BNT162b1 on days 1 and 21; 12 participants were vaccinated with 30 μg BNT162b1 on days 1 and 21; 12 participants received a 100-μg dose on day 1, and 9 participants received a placebo.	Safety, and immunogenicity.	To evaluate the safety, tolerability, and immunogenicity of each vaccine dose for each vaccine group.	Safety assessments: The pain at the site of injection was the most frequently reported local reaction seven days after the first and second vaccination doses. This response was reported by 58.3% in the 10-μg BNT162b1 group, 100.0% in the 30 -μg and 100-μg BNT162b1 groups, and 22.2% in the placebo group. Following the second dose, 16.7% of those who received the placebo as well as 83.3% and 100% of those who received 10-μg and 30-μg of BNT162b1 felt discomfort. Except for one case of severe pain following the initial dosage of 100-μg of BNT162b1, all local reactions were mild to moderate. Fever was reported by 8.3% of those who received 10-μg and 30-μg BNT162b1, and by 50.0% of those who got 100-μg BNT162b1. After the second dosage, 8.3% of those who got 10-μg BNT162b1 and 75.0% of those who received 30-μg BNT162b1 developed fever. The participants who experiencing systemic symptoms increased with dosage level and was highest after the second dose (10-μg and 30-μg groups).
						Humoral and cellular immunogenicity assessments: By 21 days after the first dose (for all three dose levels), GMCs of RBD-binding IgG were 534, 1531, and 1778 U ml^−1 in 10-μg, 30-μg and 100-μg, respectively. By 7 days after the second dose (for the 10-μg and 30-μg dose levels), RBD-binding IgG GMCs increased to 4,813 and to 27,872 U ml^−1, respectively. After 14 days, RBD-binding antibody concentrations in individuals who received the 10-μg and 30-μg dosages of BNT162b1 were 5880–16,166 U ml^−1.

AU: arbitrary units; BR: Brazil; CI: confidence interval; COVE: coronavirus efficacy; CL: Chili; CN: China; COVID-19: severe coronavirus disease 2019; GMTs: IgG binding antibody geometric mean titers; GR: Greece; IFNγ: Interferon gamma; IL-2: Interleukin-2; IL-4: Interleukin-4; IL-5: Interleukin-5; IQR: Interquartile range; LD: low dose; LD/SD cohort: low dose and a standard dose as their second dose; PE: Peru; PsVNA: pseudovirion neutralization assay; RBD: receptor-binding domain; RT-PCR: real-time reverse transcription–polymerase chain reaction; S-2P: two proline substitutions; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SARS-CoV: severe acute respiratory syndrome coronavirus; SD: standard dose; SD/SD cohort: standard dose as their first and second dose; Th1: T helper type 1; Th2: T helper type 2; TNF-α: tumor necrosis factor alpha; UK: United Kingdom; USA: United States of America; ZA: South Africa.

Table 2. Variables involved in the efficacy of mRNA, protein subunit vaccine and viral vectors vaccines against SARS-CoV-2 in people over 18 years old.

Measurement	Physiological changes	Ref.
Efficacy	The magnitude of mRNA-1273 vaccine efficacy at preventing symptomatic SARS-CoV-2 infection is higher than the efficacy observed for vaccines for respiratory viruses. However, a waning of efficacy over time has been demonstrated with other vaccines.	[11]
	A 94.1% efficacy of the mRNA-1273 vaccine was found. No evidence of vaccine-associated enhanced respiratory disease was noted.	[11]
	Greek medical professionals were found to respond quickly and strongly to the BNT162b2 vaccination in 92.2% of cases.	[35]
	For our secondary analysis of cases occurring more than 21 days after the first standard dose in participants who received only standard doses, there were 192 included cases with a vaccine efficacy of 64.1% (95% CI 50.5–73.9).	[36]
	ChAdOx1 vaccine has shown an efficacy of 70.4% after two doses and protection of 64.1% after at least one standard dose, against symptomatic disease, with no safety concerns.	[36]
	Although ZF2001 produced higher neutralizing GMTs than convalescent samples, the vaccine’s protective efficacy has yet to be shown.	[38]
	Estimated vaccination effectiveness against symptomatic disease was high in people aged 18 to 64 years (72.8%; 95% CI; 63.4 to 79.9) and 65 and older (83.5%; 95% CI; 54.2 to 94.1).	[39]
Safety	Reactions were characterized by erythema, induration, and tenderness, and they resolved over the following 4 to 5 days.	[11]
	The most common local side effect reported was mild to moderate pain at the injection site, while the most common systemic adverse effects was fatigue followed by myalgias, headache and chills. Participants with a positive history of SARS-CoV-2 infection seemed to experience more local and systemic reactions, including fever.	[35]
	Serious adverse events occurred in 168 participants, 79 of whom received ChAdOx1 nCoV-19 and 89 of whom received MenACWY or saline control. There were 175 events (84 in the ChAdOx1 nCoV-19 group and 91 in the control group), three of which were considered possibly related to either the experimental or a control vaccine.	[36]
	A potentially vaccine-related serious adverse event was reported 2 days after vaccination in South Africa in an individual who recorded fever higher than 40°C, but who recovered rapidly without an alternative diagnosis and was not admitted to hospital.	[36]
	Systemic and local adverse events occurred in more than half the participants including fatigue, chills, headache, myalgia, and pain at the injection site.	[15]
	BNT162b1 reported mild-to-moderate local reactions, primarily pain at the injection site, within 7 days after an injection. While, BNT162b1 frequently have shown mild-to-moderate fever and chills.	[37]
	Systemic events in response to BNT162b2 were milder than those in response to BNT162b1. While severe systemic events (fatigue, headache, chills, muscle pain, and joint pain) were reported in small numbers of younger recipients of BNT162b2, but no severe systemic events were reported by older recipients of this vaccine candidate.	[37]
	No participant who received either BNT162 vaccine candidate reported a grade 4 systemic event.	[37]
	Within 7 days after vaccination, most of the local and systemic reactogenicity was mild or moderate (grade 1 or 2 adverse events). The most common local adverse events were injection-site pain, redness, and itch. The most common systemic adverse events were cough, fever, and headache.	[38]
	After 28 days of either dosage, the most prevalent adverse effects in either group were general pain (8.2%), headache (6.2%), injection-site pain (6.8%), and tiredness (5.1%) in the AZD1222 group.	[39]
	Participants following their primary immunization with low-dose ChAdOx1 nCoV-19 and after the boost vaccination with the low-dose vaccine showed a similar pattern across age groups, although with fewer overall adverse reactions than the standard-dose groups.	[40]
	No volunteers of any age who received the standard dosage of ChAdOx1 nCoV-19 after the booster vaccination experienced fever. In the low-dose groups, a similar pattern of diminishing reactogenicity with increasing age was seen. Those who were given just one dose of the vaccination at random experienced similar outcomes after the first dose.	[40]
	The BNT162b1 group experiencing fatigue, headaches, chills, muscular ache, and joint pain but not those who received the placebo.	[41]
	The participants who experiencing systemic symptoms increased with dosage level and was highest after the second dose (10-μg and 30-μg groups).	[41]
Immunogenicity	A risk of acute hypersensitivity is sometimes observed with vaccines; however, no such risk was evident in the COVE trial.	[11]
	An optimal IgG cutoff score of ≥4439.4 AU ml^−1 was explicitly diagnostic of previous SARS-CoV-2 infection resulting in 95.24% sensitivity and 100% specificity via a maximum of the Youden index criterion.	[35]
	Antibody titers fluctuated in the various age groups. Post-hoc testing revealed that although titers did not significantly differ among participants aged 20–49 years, a significant decline was marked in the age group of 50–59 years, which was further accentuated in subjects aged over 60.	[36]
	Of the three doses evaluated, the 100-μg dose elicits high neutralization responses and Th1-skewed CD4 T cell responses, coupled with a reactogenicity profile that is more favorable than that of the higher dose.	[15]
	The mRNA-1273 vaccine was immunogenic, inducing robust binding antibody responses to both full-length S-2P and receptor-binding domain in all participants after the first vaccination in a time- and dose-dependent fashion. Commensurately high neutralizing antibody responses were also elicited in a dose-dependent fashion.	[15]
	Both vaccines elicited generally lower antigen-binding IgG and virus-neutralizing responses in participants 65 to 85 years of age than in those 18 to 55 years of age. Higher doses appeared to elicit somewhat higher antibody responses.	[37]
	The highest neutralization titers were measured in samples obtained on day 28 after the second dose) or on day 35 (i.e. 14 days after the second dose).	[37]
	BNT162b2 modRNA vaccine candidate has a favorable balance of reactogenicity and immunogenicity.	[37]
	At day 30 after the first immunization, in participants on the two-dose schedule, seroconversion rates of RBD-binding IgG were 1% (one of 147) in the placebo group, 59% (87 of 147) in the 25 μg group, and 65% (96 of 147) in the 50 μg group.	[38]
	No enhancement of neutralizing GMTs was found for participants receiving the high dose (50 μg) compared with those receiving the low dose (25 μg).	[38]
	The 25 μg and 50 μg doses elicited moderate levels of both Th1 (IFNγ and IL-2) and Th2 (IL-4 and IL-5) cytokine production after the immunizations.	[38]
	Locally solicited adverse events (74.1% in the AZD1222 group vs. 24.4% in the placebo group) and systemically solicited adverse events (71.6% vs. 53.0% overall) were more common in the AZD1222 group than in the placebo group.	[39]
	In all age groups, side events occurred less often after the second dosage, and the response was more pronounced in people aged between 18 and 64 years old.	[39]
	Within each age group, no significant differences were seen in neutralization titers between LD and SD vaccine recipients at the same timepoint (18–55 years p = 0.33, 56–69 years p = 0.12, ≥70 years p = 0.62).	[40]
	Highly higher RBD-binding antibody concentrations persisted in subjects who received the 10-μg and 30-μg dosages of BNT162b1 until the last time point assessed (14 days after the second dose).	[41]
	One dose of 100 g BNT162b1 was given to subjects, and after 21 days, RBD-binding antibody concentrations did not increase any more.	[41]

AU ml⁻¹: arbitrary units per milliliter; COVE: coronavirus efficacy; GMTs: IgG binding antibody geometric mean titers; IFNγ: interferon gamma; IL-2: interleukin-2; IL-4: interleukin-4; IL-5: interleukin-5; LD: low dose; MenACWY: meningitis ACWY vaccine; RBD: receptor-binding domain; S-2P: two proline substitutions; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SD: standard dose; Th1: T helper type 1; Th2: T helper type 2.

Figure 1. Prisma flow diagram.

Table 3. Adverse reactions after vaccination.

Ref.	Age	Vaccine	Vaccination schedule	Frequency of adverse reaction
[11]	18–<65 years old	mRNA-1273 (100 µg)	After two-dose schedule	Any: 23.4%^‡
	>65 years old		After two-dose schedule	Any: 25.4%^‡
[36]	18–>70 years old	AZD1222	NR	Any: 08%
[15]	18–55 years old	mRNA-1273 (25 mcg)	Prime	Mild: 20%^†
			Prime	Moderate: 13.3%^†
			Booster	Mild: 30.8%^†
			Booster	Moderate: 23.1%^†
		mRNA-1273 (100 mcg)	Prime	Mild: 53.3%^†
			Prime	Moderate: 13.3%^†
			Booster	Mild: 20%^†
			Booster	Moderate: 80%^†
		mRNA-1273 (250 mcg)	Prime	Mild: 26.7%^†
			Prime	Moderate: 26.7%^†
			Booster	Mild: 14.3%^†
			Booster	Moderate: 64.3%^†
[37]	18–55 years old	BNT162b1 (10 µg)	After two-dose schedule	Any: 50%^‡
		BNT162b1 (20 µg)	After two-dose schedule	Any: 41.7%^‡
		BNT162b1 (30 µg)	After two-dose schedule	Any: 50%^‡
		BNT162b1 (100 µg)	After one-dose schedule	Any: 58.3%^‡
	65–85 years old	BNT162b1 (10 µg)	After two-dose schedule	Any: 58.3%^‡
		BNT162b1 (20 µg)	After two-dose schedule	Any: 58.3%^‡
		BNT162b1 (30 µg)	After two-dose schedule	Any: 25%^‡
	18–55 years old	BNT162b2 (10 µg)	After two-dose schedule	Any: 33.3%^‡
		BNT162b2 (20 µg)	After two-dose schedule	Any: 41.7%^‡
		BNT162b2 (30 µg)	After two-dose schedule	Any: 41.7%^‡
	65–85 years old	BNT162b2 (10 µg)	After two-dose schedule	Any: 8.3%^‡
		BNT162b2 (20 µg)	After two-dose schedule	Any: 16.7%^‡
		BNT162b2 (30 µg)	After two-dose schedule	Any: 25%^‡
[38]	18–59 years	ZF2001 (25 µg)	After two-dose schedule	Any: 29%^#
		ZF2001 (25 µg)	After three-dose schedule	Any: 48%^#
		ZF2001 (50 µg)	After two-dose schedule	Any: 33%^#
		ZF2001 (50 µg)	After three-dose schedule	Any: 43%^#
[39]	18–>65 years	AZD1222	After two-dose schedule	Mild: 23.1%^‡
			After two-dose schedule	Moderate: 5.1%^‡
			After two-dose schedule	Severe: 0.2%^‡
[40]	18–55 years old	AZD1222 (LD/LD)	Prime	Any: 90%^†
			Booster	Any: 76%^†
	56–69 years old	AZD1222 (LD/LD)	Prime	Any: 73%^†
			Booster	Any: 60%^†
	>70 years old	AZD1222 (LD/LD)	Prime	Any: 61%^†
			Booster	Any: 44%^†
	18–55 years old	AZD1222 (SD/SD)	Prime	Any: 98%^†
			Booster	Any: 86%^†
	56–69 years old	AZD1222 (SD/SD)	Prime	Any: 93%^†
			Booster	Any: 97%^†
	>70 years old	AZD1222 (SD/SD)	Prime	Any: 80%^†
			Booster	Any: 71%^†
[41]	19–54 years	BNT162b1 (10 µg)	After two-dose schedule	Any: 50%
		BNT162b1 (30 µg)	After two-dose schedule	Any: 50%
		BNT162b1 (100 µg)	After one-dose schedule	Any: 58%

NR: Not reported; ^‡Reactions in the 28 days after vaccination; ^#adverse events within 30 days; ^†Reactions in the 7 days after vaccination.

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