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Preplanned Studies: Immunogenicity and Safety of Homologous Booster Doses of CoronaVac COVID-19 Vaccine in Elderly Individuals Aged 60 Years and Older: A Dosing Interval Study — Yunnan Province, China, 2021–2022

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  • Summary

    What is already known about this topic?

    Neutralization levels induced by inactivated vaccines rapidly wane after primary immunization, and a homologous booster can recall specific immune memory, resulting in a remarkable increase in antibody concentration. The optimal interval between primary and booster doses has yet to be determined.

    What is added by this report?

    Booster doses given at three months or more after the two-dose regimen of the CoronaVac COVID-19 vaccine in elderly individuals aged 60 years and older triggered good immune responses. The geometric mean titers of neutralizing antibody on Day 14 after the booster doses increased by 13.3–26.2 fold of baseline levels, reaching 105.45–193.59 in groups with different intervals (e.g., 3, 4, 5, and 6 months).

    What are the implications for public health practice?

    A 4- to 5-month interval between receiving the primary and booster series of CoronaVac could be an alternative to the 6-month interval in order to promote vaccine-induced immunity in elderly individuals. The findings support the optimization of booster immunization strategies.

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  • [1] McMenamin ME, Nealon J, Lin Y, Wong JY, Cheung JK, Lau EHY, et al. Vaccine effectiveness of one, two, and three doses of BNT162b2 and CoronaVac against COVID-19 in Hong Kong: a population-based observational study. Lancet Infect Dis 2022;22(10):1435 − 43. http://dx.doi.org/10.1016/S1473-3099(22)00345-0CrossRef
    [2] Huang ZY, Xu SF, Liu JC, Wu LL, Qiu J, Wang N, et al. Effectiveness of inactivated and Ad5-nCoV COVID-19 vaccines against SARS-CoV-2 Omicron BA. 2 variant infection, severe illness, and death. BMC Med 2022;20(1):400. http://dx.doi.org/10.1186/s12916-022-02606-8CrossRef
    [3] Rodewald L, Wu D, Yin ZD, Feng ZJ. Vaccinate with confidence and finish strong. China CDC Wkly 2022;4(37):828 − 31. http://dx.doi.org/10.46234/ccdcw2022.172CrossRef
    [4] Kwok SLL, Cheng SMS, Leung JNS, Leung K, Lee CK, Peiris JM, et al. Waning antibody levels after COVID-19 vaccination with mRNA Comirnaty and inactivated CoronaVac vaccines in blood donors, Hong Kong, April 2020 to October 2021. Euro Surveill 2022;27(2):2101197. http://dx.doi.org/10.2807/1560-7917.ES.2022.27.2.2101197CrossRef
    [5] Zeng G, Wu QH, Pan HX, Li MJ, Yang J, Wang L, et al. Immunogenicity and safety of a third dose of CoronaVac, and immune persistence of a two-dose schedule, in healthy adults: interim results from two single-centre, double-blind, randomised, placebo-controlled phase 2 clinical trials. Lancet Infect Dis 2022;22(4):483 − 95. http://dx.doi.org/10.1016/S1473-3099(21)00681-2CrossRef
    [6] Xin QQ, Wu QH, Chen XH, Han BH, Chu K, Song Y, et al. Six-month follow-up of a booster dose of CoronaVac in two single-centre phase 2 clinical trials. Nat Commun 2022;13(1):3100. http://dx.doi.org/10.1038/s41467-022-30864-wCrossRef
    [7] Shrotri M, Navaratnam AMD, Nguyen V, Byrne T, Geismar C, Fragaszy E, et al. Spike-antibody waning after second dose of BNT162b2 or ChAdOx1. Lancet 2021;398(10298):385 − 7. http://dx.doi.org/10.1016/S0140-6736(21)01642-1CrossRef
    [8] Jacobsen H, Katzmarzyk M, Higdon MM, Jiménez VC, Sitaras I, Bar-Zeev N, et al. Post-vaccination neutralization responses to Omicron sub-variants. Vaccines 2022;10(10):1757. http://dx.doi.org/10.3390/vaccines10101757CrossRef
    [9] Juno JA, Wheatley AK. Boosting immunity to COVID-19 vaccines. Nat Med 2021;27(11):1874 − 5. http://dx.doi.org/10.1038/s41591-021-01560-xCrossRef
    [10] Zhao X, Li DD, Ruan WJ, Chen ZH, Zhang R, Zheng AQ, et al. Effects of a prolonged booster interval on neutralization of omicron variant. N Engl J Med 2022;386(9):894 − 6. http://dx.doi.org/10.1056/NEJMc2119426CrossRef
    [11] Assawakosri S, Kanokudom S, Suntronwong N, Auphimai C, Nilyanimit P, Vichaiwattana P, et al. Neutralizing activities against the omicron variant after a heterologous booster in healthy adults receiving two doses of CoronaVac vaccination. J Infect Dis 2022;226(8):1372 − 81. http://dx.doi.org/10.1093/infdis/jiac092CrossRef
    [12] Canetti M, Barda N, Gilboa M, Indenbaum V, Asraf K, Gonen T, et al. Six-month follow-up after a fourth BNT162b2 vaccine dose. N Engl J Med 2022;387(22):2092 − 4. http://dx.doi.org/10.1056/NEJMc2211283CrossRef
    [13] Bar-On YM, Goldberg Y, Mandel M, Bodenheimer O, Amir O, Freedman L, et al. Protection by a fourth dose of BNT162b2 against omicron in Israel. N Engl J Med 2022;386(18):1712 − 20. http://dx.doi.org/10.1056/NEJMoa2201570CrossRef
    [14] Gazit S, Saciuk Y, Perez G, Peretz A, Pitzer VE, Patalon T. Short term, relative effectiveness of four doses versus three doses of BNT162b2 vaccine in people aged 60 years and older in Israel: retrospective, test negative, case-control study. BMJ 2022;377:e071113. http://dx.doi.org/10.1136/bmj-2022-071113CrossRef
  • FIGURE 1.  Neutralizing antibody levels to live SARS-CoV-2 before and after the booster vaccination in different interval groups.

    Note: Numbers at the bottom of the bars are GMTs, and error bars indicate 95% CIs. Dots are reciprocal neutralizing antibody titers for individuals in the per-protocol population. Numbers above the short horizontal lines are P values for comparisons among the 3-month group, 4-month group, 5-month group, and 6-month group using ANOVA with log-transformation. Bonferroni correction was performed as a post hoc test if the variance was significant. Only P values indicating significant differences are marked. The dotted horizontal line represents the limit of detection (1∶4). Titers lower than the limit of detection are presented as half of that.

    Abbreviation: SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; GMTs=geometric mean titers; CIs=confidence intervals; ANOVA=analysis of variance.

    TABLE 1.  Baseline demographic characteristics of participants who received booster doses of CoronaVac COVID-19 vaccine.

    Characteristics3-month group
    (n=101)
    4-month group
    (n=99)
    5-month group
    (n=100)
    6-month group
    (n=100)
    Total
    (N=400)
    Sex
    Male43 (43%)49 (49%)54 (54%)52 (52%)198 (50%)
    Female58 (57%)50 (51%)46 (46%)48 (48%)202 (50%)
    Age group (years)
    60–7074 (73%)87 (88%)81 (81%)85 (85%)327 (82%)
    70–8026 (26%)11 (11%)19 (19%)15 (15%)71 (18%)
    80+1 (1%)1 (1%)0 (0%)0 (0%)2 (1%)
    BMI (kg/m2, IQR)22.58
    (20.86, 24.77)
    23.71
    (21.00, 25.98)
    22.82
    (20.83, 24.91)
    22.44
    (20.67, 24.15)
    22.80
    (20.83, 24.98)
    Ethnicity
    Han72 (71%)76 (77%)68 (68%)96 (96%)312 (78%)
    Others29 (29%)23 (23%)32 (32%)4 (4%)88 (22%)
    Comorbidity
    At least one40 (40%)42 (42%)36 (36%)24 (24%)142 (36%)
    Hypertension32 (32%)29 (29%)28 (28%)13 (13%)102 (26%)
    Diabetes6 (6%)7 (7%)5 (5%)2 (2%)20 (5%)
    Cerebral infarction1 (1%)9 (9%)5 (5%)4 (4%)19 (5%)
    Coronary heart disease4 (4%)3 (3%)3 (3%)0 (0%)10 (3%)
    Hyperthyroidism0 (0%)1 (1%)1 (1%)1 (1%)3 (1%)
    Others6 (6%)6 (6%)3 (3%)12 (12%)27 (7%)
    Interval between 3rd and
    2nd doses (days, IQR)
    110.00
    (98.00, 117.00)
    132.00
    (131.00, 132.00)
    166.00
    (163.00, 168.00)
    185.00
    (185.00, 185.00)
    153.50
    (117.00, 172.75)
    Note: Data are presented as the median (IQR, interquartile range) or number (percentage). Continuous variables were compared using the Kruskal‒Wallis H-test. Categorical variables were compared using the chi-square test or Fisher’s exact test.
    Abbreviation: BMI=body mass index.
    Download: CSV

    TABLE 2.  GMTs of neutralizing antibodies in different interval groups at different time points.

    Time points3-month group4-month group5-month group6-month groupP value*
    Baseline (Pre-booster)
    No. of participantsn=101n=99n=100n=100
    GMT (95% CI)8.06
    (6.68, 9.72)
    7.98
    (6.56, 9.70)
    7.40
    (6.13, 8.94)
    5.26
    (4.43, 6.25)
    0.0036
    Day 14 after dose 3
    No. of participantsn=101n=98n=98n=99
    GMT (95% CI)105.45
    (86.14, 129.08)
    187.31
    (152.99, 229.33)
    193.59
    (151.84, 246.82)
    135.52
    (111.32, 164.99)
    <0.0001
    Fold increases vs. baseline (95% CI)13.26
    (10.55, 16.67)
    23.09
    (18.31, 29.11)
    25.82
    (19.53, 34.14)
    26.22
    (20.82, 33.01)
    0.17
    Day 28 after dose 3
    No. of participantsn=97n=97n=96n=92
    GMT (95% CI)90.57
    (73.53, 111.54)
    138.81
    (113.26, 170.11)
    169.01
    (132.97, 214.82)
    123.64
    (100.93, 151.46)
    0.0006
    Day 180 after dose 3
    No. of participantsn=87n=85n=91n=94
    GMT (95% CI)7.21
    (6.05, 8.58)
    10.24
    (8.51, 12.32)
    15.45
    (12.23, 19.52)
    9.82
    (8.03, 12.01)
    <0.0001
    Fold decreases vs. Day 14 (95% CI)14.99
    (12.62, 17.79)
    17.72
    (14.51, 21.64)
    12.29
    (9.97, 15.16)
    14.26
    (11.85, 17.15)
    0.60
    Note: GMT was calculated based on log-transformed data.
    Abbreviation: GMTs=geometric mean titers; CI=confidence interval; ANOVA=analysis of variance.
    * ANOVA with log-transformation (GMT) was used to detect differences among the four groups. Differences between groups were assessed by t test on log-transformed data.
    Download: CSV

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Immunogenicity and Safety of Homologous Booster Doses of CoronaVac COVID-19 Vaccine in Elderly Individuals Aged 60 Years and Older: A Dosing Interval Study — Yunnan Province, China, 2021–2022

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Summary

What is already known about this topic?

Neutralization levels induced by inactivated vaccines rapidly wane after primary immunization, and a homologous booster can recall specific immune memory, resulting in a remarkable increase in antibody concentration. The optimal interval between primary and booster doses has yet to be determined.

What is added by this report?

Booster doses given at three months or more after the two-dose regimen of the CoronaVac COVID-19 vaccine in elderly individuals aged 60 years and older triggered good immune responses. The geometric mean titers of neutralizing antibody on Day 14 after the booster doses increased by 13.3–26.2 fold of baseline levels, reaching 105.45–193.59 in groups with different intervals (e.g., 3, 4, 5, and 6 months).

What are the implications for public health practice?

A 4- to 5-month interval between receiving the primary and booster series of CoronaVac could be an alternative to the 6-month interval in order to promote vaccine-induced immunity in elderly individuals. The findings support the optimization of booster immunization strategies.

  • 1. Yunnan Provincial Center for Disease Control and Prevention, Kunming City, Yunnan Province, China
  • 2. Sinovac Biotech Co., Ltd., Beijing Municipality, China
  • 3. School of Public Health, Fudan University, Key Laboratory of Public Health Safety, Ministry of Education, Shanghai Municipality, China
  • 4. Yongde County Center for Disease Control and Prevention, Lincang City, Yunnan Province, China
  • 5. Sinovac Life Sciences, Beijing Municipality, China
  • Corresponding authors:

    Hongjie Yu, yhj@fudan.edu.cn

    Xiaoqiang Liu, liuxqms@163.com

    Gang Zeng, zengg@sinovac.com

    Online Date: February 10 2023
    Issue Date: February 10 2023
    doi: 10.46234/ccdcw2023.023
  • Vaccination has been proven to be highly effective in reducing the burden of coronavirus disease 2019 (COVID-19) in the context of emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants based on real-world evidence (1-2). With the efforts of the whole of Chinese society, vaccine coverage of primary immunization has reached 90% (3). As neutralization antibody levels rapidly decline after primary immunization (4), especially for vulnerable populations, determining the optimal interval between primary and booster series is an urgent step in promoting vaccine-induced population immunity. To explore the immunogenicity, immune persistence, and safety of homologous booster doses of CoronaVac administered at 3-month, 4-month, 5-month, and 6-month intervals in elderly individuals aged 60 years and older, we conducted a single-center, open-label trial in Yongde County, Yunnan Province. We found that booster doses given at three months or more after the two-dose regimen of CoronaVac in elderly individuals aged 60 years and older could trigger good immune responses, especially at four to six months. This would be conducive to optimizing intervals for the booster vaccination strategy.

    In this single-center, open-label clinical trial conducted in Yongde County, Yunnan Province, China, participants aged 60 years and over who had received two doses of CoronaVac three to six months prior were recruited. The detailed inclusion and exclusion criteria are listed in Supplementary Table S1. Eligible participants were assigned to four groups according to the time elapsed after their two-dose immunization, namely, the 3-month, 4-month, 5-month, and 6-month interval groups. All participants provided written informed consent prior to enrollment. The study protocol and informed consent were approved by the Ethics Committee of Yunnan CDC (#2021-14). This trial was registered with ClinicalTrials.gov, NCT05398926.

    Blood samples were collected from participants before booster administration and on Days 14, 28, and 180 after booster doses to assess immunogenicity. Neutralizing antibody levels against live SARS-CoV-2 (virus strain SARS-CoV-2/human/CHN/CN1/2020, GenBank accession number MT407649.1) were quantified using a previously described micro cytopathogenic effect assay (5-6). Titers lower than the limit of detection (1∶4) were treated as half the limit of detection. Participants were observed for 30 minutes after vaccine administration in case of any immediate reactions. Solicited local and systemic adverse events within 7 days, unsolicited adverse events within 28 days, and serious adverse events within 6 months were collected after booster doses. All adverse events were graded according to China National Medical Products Administration guidelines and coded by the Medical Dictionary for Regulatory Activities (MedDRA 25.0) System Organ Class. The causal relationships between adverse events and vaccination were assessed by the investigators and an expert committee organized by CDC.

    The primary outcomes included geometric mean titers (GMTs) of neutralizing antibodies against live SARS-CoV-2 on Day 14, Day 28, and Day 180, as well as any vaccine-related adverse events within 28 days after booster doses. The incidence of solicited adverse events within 7 days and serious adverse events reported during the 6-month follow-up were evaluated as secondary safety endpoints. Post hoc analysis assessed fold increases in antibody levels before administration to Day 14 and fold decreases from Day 14 to Day 180 after booster doses in each group. The immunogenic outcomes were evaluated in the per-protocol set, comprising participants who completed their assigned vaccination and had available blood samples at prespecified time points. Participants who received booster doses were included in the safety analysis.

    We used the Pearson χ2 test or Fisher’s exact test for categorical outcomes and the Clopper-Pearson method for corresponding 95% confidence intervals (CIs). GMTs and corresponding 95% CIs were calculated on the basis of the standard normal distribution of the log-transformed antibody titers. Fold increases/decreases in antibody levels were calculated as the geometric mean of the ratios of paired sera at two visits. Analysis of variance (ANOVA) with log-transformation was used to test the differences between groups and between follow-up times. Comparisons were performed between groups or by group t tests with log-transformation. Bonferroni correction was performed as a post hoc test if variance was significant. Subgroup analyses of immunogenicity were conducted by sex and self-reported comorbidity status. Hypothesis testing was two-sided, and a P value <0.05 was considered to indicate statistical significance. We used R (version 4.2.1; R Core Team, Vienna, Austria) for all analyses.

    Between December 6 and 24, 2021, a total of 400 participants were enrolled in the study and allocated to four groups according to the interval between their second and booster doses; 101, 99, 100, and 100 participants were allocated to the 3-month, 4-month, 5-month, and 6-month groups, respectively (Supplementary Figure S1). The median age of the participants was 65 [interquartile range (IQR), 63–68] years, and the distribution was balanced among groups. Of the 400 participants, 198 (50%) were male, and 312 (78%) were ethnically Han. Hypertension was the most common comorbidity, present in 102 (26%) participants. The demographic characteristics are detailed in Table 1.

    Characteristics3-month group
    (n=101)
    4-month group
    (n=99)
    5-month group
    (n=100)
    6-month group
    (n=100)
    Total
    (N=400)
    Sex
    Male43 (43%)49 (49%)54 (54%)52 (52%)198 (50%)
    Female58 (57%)50 (51%)46 (46%)48 (48%)202 (50%)
    Age group (years)
    60–7074 (73%)87 (88%)81 (81%)85 (85%)327 (82%)
    70–8026 (26%)11 (11%)19 (19%)15 (15%)71 (18%)
    80+1 (1%)1 (1%)0 (0%)0 (0%)2 (1%)
    BMI (kg/m2, IQR)22.58
    (20.86, 24.77)
    23.71
    (21.00, 25.98)
    22.82
    (20.83, 24.91)
    22.44
    (20.67, 24.15)
    22.80
    (20.83, 24.98)
    Ethnicity
    Han72 (71%)76 (77%)68 (68%)96 (96%)312 (78%)
    Others29 (29%)23 (23%)32 (32%)4 (4%)88 (22%)
    Comorbidity
    At least one40 (40%)42 (42%)36 (36%)24 (24%)142 (36%)
    Hypertension32 (32%)29 (29%)28 (28%)13 (13%)102 (26%)
    Diabetes6 (6%)7 (7%)5 (5%)2 (2%)20 (5%)
    Cerebral infarction1 (1%)9 (9%)5 (5%)4 (4%)19 (5%)
    Coronary heart disease4 (4%)3 (3%)3 (3%)0 (0%)10 (3%)
    Hyperthyroidism0 (0%)1 (1%)1 (1%)1 (1%)3 (1%)
    Others6 (6%)6 (6%)3 (3%)12 (12%)27 (7%)
    Interval between 3rd and
    2nd doses (days, IQR)
    110.00
    (98.00, 117.00)
    132.00
    (131.00, 132.00)
    166.00
    (163.00, 168.00)
    185.00
    (185.00, 185.00)
    153.50
    (117.00, 172.75)
    Note: Data are presented as the median (IQR, interquartile range) or number (percentage). Continuous variables were compared using the Kruskal‒Wallis H-test. Categorical variables were compared using the chi-square test or Fisher’s exact test.
    Abbreviation: BMI=body mass index.

    Table 1.  Baseline demographic characteristics of participants who received booster doses of CoronaVac COVID-19 vaccine.

    The GMTs of neutralizing antibodies before administration of booster doses were 8.06 (95% CI: 6.68–9.72) in the 3-month group, 7.98 (95% CI: 6.56–9.70) in the 4-month group, 7.40 (95% CI: 6.13–8.94) in the 5-month group, and 5.26 (95% CI: 4.43–6.25) in the 6-month group, which were significantly different between the 3-month and 6-month (P=0.012), and 4-month and 6-month groups (P=0.008), respectively. Remarkable increases in GMTs were observed in all groups on Day 14 after the boosters, reaching 105.45 (95% CI: 86.14–129.08), 187.31 (95% CI: 152.99–229.33), 193.59 (95% CI: 151.84–246.82), and 135.52 (95% CI: 111.32–164.99) in the four groups (P<0.0001), respectively. Only the antibody levels in the 4-month and 5-month groups significantly exceeded those in the 3-month group (both P<0.0001) and there were no significant differences in neutralizing antibody levels between the other three groups and the 6-month group (P=0.57, 0.20, 0.11), which was the recommended minimum interval between primary and booster regimens in China before December 2022. No significant differences in fold increases were observed among the four groups. A declining tendency in GMT values was observed in all groups from Day 14 to Day 28 after the booster doses. GMTs by six months after the boosters were highest in the 5-month group (15.45, 95% CI: 12.23–19.52), followed by the 4-month group (10.24, 95% CI: 8.51–12.32), the 6-month group (9.82, 95% CI: 8.03–12.01), and the 3-month group (7.21, 95% CI: 6.05–8.58) (Table 2 and Figure 1). The fold decreases from Day 14 to Day 180 after booster doses were similar among the four groups (Table 2). When compared between follow-up times, there was no significant difference between baseline and Day 180, or between Day 14 and Day 28 in all groups, except the 4-month group, in which the GMT on Day 14 was significantly different from Day 28 after the booster doses. In subgroup analyses, no significant differences in neutralizing antibodies were found between sex groups and comorbidity status (Supplementary Figures S2 and S3).

    Time points3-month group4-month group5-month group6-month groupP value*
    Baseline (Pre-booster)
    No. of participantsn=101n=99n=100n=100
    GMT (95% CI)8.06
    (6.68, 9.72)
    7.98
    (6.56, 9.70)
    7.40
    (6.13, 8.94)
    5.26
    (4.43, 6.25)
    0.0036
    Day 14 after dose 3
    No. of participantsn=101n=98n=98n=99
    GMT (95% CI)105.45
    (86.14, 129.08)
    187.31
    (152.99, 229.33)
    193.59
    (151.84, 246.82)
    135.52
    (111.32, 164.99)
    <0.0001
    Fold increases vs. baseline (95% CI)13.26
    (10.55, 16.67)
    23.09
    (18.31, 29.11)
    25.82
    (19.53, 34.14)
    26.22
    (20.82, 33.01)
    0.17
    Day 28 after dose 3
    No. of participantsn=97n=97n=96n=92
    GMT (95% CI)90.57
    (73.53, 111.54)
    138.81
    (113.26, 170.11)
    169.01
    (132.97, 214.82)
    123.64
    (100.93, 151.46)
    0.0006
    Day 180 after dose 3
    No. of participantsn=87n=85n=91n=94
    GMT (95% CI)7.21
    (6.05, 8.58)
    10.24
    (8.51, 12.32)
    15.45
    (12.23, 19.52)
    9.82
    (8.03, 12.01)
    <0.0001
    Fold decreases vs. Day 14 (95% CI)14.99
    (12.62, 17.79)
    17.72
    (14.51, 21.64)
    12.29
    (9.97, 15.16)
    14.26
    (11.85, 17.15)
    0.60
    Note: GMT was calculated based on log-transformed data.
    Abbreviation: GMTs=geometric mean titers; CI=confidence interval; ANOVA=analysis of variance.
    * ANOVA with log-transformation (GMT) was used to detect differences among the four groups. Differences between groups were assessed by t test on log-transformed data.

    Table 2.  GMTs of neutralizing antibodies in different interval groups at different time points.

    Figure 1. 

    Neutralizing antibody levels to live SARS-CoV-2 before and after the booster vaccination in different interval groups.

    Note: Numbers at the bottom of the bars are GMTs, and error bars indicate 95% CIs. Dots are reciprocal neutralizing antibody titers for individuals in the per-protocol population. Numbers above the short horizontal lines are P values for comparisons among the 3-month group, 4-month group, 5-month group, and 6-month group using ANOVA with log-transformation. Bonferroni correction was performed as a post hoc test if the variance was significant. Only P values indicating significant differences are marked. The dotted horizontal line represents the limit of detection (1∶4). Titers lower than the limit of detection are presented as half of that.

    Abbreviation: SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; GMTs=geometric mean titers; CIs=confidence intervals; ANOVA=analysis of variance.

    Solicited adverse events within 7 days were graded as mild (Grade 1) or moderate (Grade 2) in all groups (Supplementary Table S2). The proportions of participants who experienced vaccine-related adverse events within 28 days after the booster dose were 9% in the 3-month group, 8% in the 4-month group, 14% in the 5-month group, and 4% in the 6-month group, with no significant difference among groups (P=0.10; Supplementary Table S3). During the six-month follow-up period after booster doses, no vaccine-related serious adverse events were recorded (Supplementary Table S4).

    • Our study found that neutralization antibody levels continued to decline at three months post vaccination with a two-dose regimen of CoronaVac in elderly individuals aged 60 years and older, were sustained through months three to five, and exhibited an obvious reduction at six months. Waning of antibody levels in infection-naive individuals around a one- to three-month period after the second dose administration has been identified in most COVID-19 vaccines (7), which is associated with reduced protection, especially against emerging variants due to immune escape (8). The significantly lower antibody level in the 6-month group than other groups could prove that it would be preferable to provide the booster doses no more than six months after primary immunization to avoid the increasing risk of infection among elderly individuals.

      None of the participants experienced natural infections before or during the study period, and there were no local outbreaks in Yunnan Province. Booster doses of inactivated vaccines given at three to six months after primary immunization could recall specific immune memory and rebound neutralization antibody levels in elderly individuals. Antibody titers in the 5-month group were numerically higher than those in the other three groups over the six-month follow-up after booster doses, but there was no significant difference between the 4-month, 5-month, and 6-month groups on Day 14 and 28 after the booster doses. Prolonged intervals between doses could facilitate the affinity maturation of memory B cells (9) and several studies indicated that longer intervals before the booster dose elicited better neutralizing antibody levels (10-11), which was consistent with relatively poor immune responses in the 3-month group in our study. Our results showed that a 4- to 5-month interval between receiving the primary and booster series of CoronaVac would be an alternative choice to the 6-month interval to promote vaccine-induced immunity for elderly individuals.

      On Day 180 after the first booster doses, GMTs declined to nearly undetectable levels. Previous follow-up studies (6,12) also reported a decreasing tendency after the first booster doses, suggesting that a second booster should be administered in a timely manner to provide extra protection against waning of protective antibodies. Real-world studies have reported the relative effectiveness of the second booster, indicating additional protection compared to the first booster (13-14).

      This study has several limitations. First, we did not assess T-cell responses and neutralization tests in vitro against emerging variants of concern, particularly Omicron and its subvariants. Second, the proportion of participants aged 80 years or older and those with severe comorbidities was too small to determine immunogenicity for this older age group and high-risk population. Third, we did not assess the neutralizing antibody level between 28 and 180 days after booster doses to quantify the specific waning pattern.

      In summary, homologous inactivated boosters after the two-dose regimen showed good immunogenicity and safety profiles in elderly individuals aged 60 years and older. Since November 29, 2022, the recommended minimum interval between the primary and booster series of COVID-19 vaccines in China has been shortened to three months for elderly individuals aged 60 years and older. Our results also imply that a 4- to 5-month interval between receiving the primary and booster series of CoronaVac could be an alternative choice to the 6-month interval to promote vaccine-induced immunity for elderly individuals. Further studies with more follow-up visits are needed to better understand immunogenicity after the first booster immunization and to help optimize the second booster immunization strategy. Real-world studies on the severity of infection and booster-dose effectiveness should be conducted.

    • This study was supported by Sinovac Biotech Ltd. HT.Y., X.M., TT.Z., X.L. and G.Z. formulated the study design, performed the data collection and revised the manuscript. TY.Z., Q.W. and HJ.Y. performed data analysis, interpretation and writing of the manuscript. C.W., Z.Y., M.L. and Y.Z. collected the data and revised the manuscript. Y.H. carried out the laboratory assays and revised the manuscript. All authors had full access to all of the data (including statistical reports and tables) in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors had final responsibility for the decision to submit the manuscript for publication.

    • HJ.Y. has received research funding from Sanofi Pasteur, GlaxoSmithKline, Yichang HEC Changjiang Pharmaceutical Company, Shanghai Roche Pharmaceutical Company and Sinovac Biotech Ltd. X.M., TT.Z. and G.Z. are employees of Sinovac Biotech and Y.H. is an employee of Sinovac Life Sciences. The remaining authors declare no competing interests.

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