Safety, immune response, and long COVID after inactivated COVID-19 vaccine boosters in older Chinese adults

The emergence and global spread of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a major public health challenge (1, 2). Adults aged ≥60 years face heightened SARS-CoV-2 infection risks related to physiological decline, chronic comorbidities, and compromised immune function, which collectively contribute to increased disease severity, complications, and mortality (3, 4).

There is accumulating evidence that SARS-CoV-2 vaccination confers protective effects in this population (5, 6). Inactivated SARS-CoV-2 vaccines such as CoronaVac and Covilo are widely used domestically and internationally, with several clinical trials demonstrating their general safety and efficacy in older populations (7). Specifically, in adults aged ≥60 years, CoronaVac and Covilo have achieved seroconversion rates of 98% and 100%, respectively, with adverse reactions predominantly ranging from mild to moderate in severity (8, 9). However, in observational studies from Malaysia and China, vaccine effectiveness against infection declined significantly within 3–6 months after primary immunization. This trend is consistent across both mRNA (e.g., BNT162b2) and inactivated vaccines. CoronaVac has also shown reduced protection against severe outcomes, such as intensive care unit admission (10, 11). Multiple diverse studies reported waning immunity within 2–6 months post primary immunization (12–14), particularly in older adults, who may face nearly twice the risk of severe COVID-19 after this decline (15–17). Current evidence suggests that vaccination intervals modulate the magnitude and persistence of vaccine-induced immunity. Administering booster doses within this 2- to 6-month window helps sustain adequate immune protection, which is of paramount importance for elderly and high-risk populations (18).

This challenge is further compounded by SARS-CoV-2 genetic diversity, with emerging variants exhibiting reduced susceptibility to neutralizing antibodies elicited by primary vaccination (19, 20). Despite widespread vaccination, continuous viral evolution, exemplified by the Omicron variant, has enhanced the ability of the virus to evade neutralizing antibodies, resulting in breakthrough infections (17, 21).

Post-acute sequelae of COVID-19 or long COVID has emerged as a persistent global public health challenge, affecting millions worldwide (22). As defined by the World Health Organization, long COVID refers to new, recurring, or persistent symptoms that develop within 3 months of an initial, acute SARS-CoV-2 infection and last for at least 2 months, encompassing over 200 manifestations (e.g., fatigue, dyspnea, cognitive impairment, musculoskeletal pain) that impair daily functioning and quality of life (22). Accumulating evidence indicates that long COVID can occur regardless of acute disease severity, but older and immunocompromised individuals face heightened risk attributable to age-related immunosenescence, inflammaging, and comorbidities (23).

Following the adjustment of China’s COVID-19 prevention and control policies in late 2022, the country experienced a large-scale wave of first infections. During that period, older and immunocompromised individuals were exposed not only to heightened risks of acute infection but also to a markedly increased likelihood of developing long COVID (24–26).

Here, we conducted a prospective cohort investigation of 450 adults aged ≥60 years, assigned to one of three schedules of an inactivated SARS-CoV-2 vaccine (Covilo or CoronaVac), with 12-month follow-up to evaluate vaccine immunogenicity, safety, and protective efficacy against acute infection and long COVID. The aim was to strengthen clinical evidence for inactivated vaccines in older populations and provide a scientific basis for refining targeted immunization strategies.

SARS-CoV-2 infection poses a disproportionately high threat to adults aged 60 years and above, with this population facing elevated risks of severe COVID-19, hospitalization and post-acute sequelae of COVID-19 (long COVID) due to age-related immune senescence, chronic comorbidities and impaired physiological function. Inactivated COVID-19 vaccines have been widely deployed for primary and booster immunization globally, and mounting evidence has confirmed their basic safety and immunogenicity in older adults (19). However, critical questions remain about the optimal booster interval, the durability of immune responses induced by different vaccination schedules, and the protective effects against COVID-19 symptoms and long COVID in this vulnerable group (27, 28). In this prospective cohort study of 450 elderly individuals in Zhejiang Province, we systematically evaluated the safety, humoral immune responses and clinical outcomes of two inactivated vaccines (CoronaVac and Covilo) under three distinct dosing schedules, and our findings provide valuable real-world evidence for refining booster vaccination strategies tailored to older adults.

The overall safety profile of the two inactivated vaccines was favorable in our study, with the incidence of vaccine-related adverse reactions ranging from 0.0% to 8.0% across all subgroups, and no severe adverse events reported. This is consistent with previous clinical trials and real-world studies of inactivated COVID-19 vaccines in elderly populations, where adverse reactions are predominantly mild and self-limiting (18). This aligns with observations from a homologous CoronaVac booster study in Yunnan, China, where injection-site pain was the most frequently reported local adverse event, and systemic reactions were rare (29). Systemic adverse reactions in our study were only observed in small subsets (Covilo-S2 with allergy, CoronaVac-S3 with fever), accounting for just 1.3% of participants in each affected subgroup, further confirming that inactivated vaccine boosters are well-tolerated by older adults (29).

Humoral immune responses showed distinct patterns across vaccination schedules and vaccine types (30, 31), with the 4–6 month interval third booster dose (S3) consistently inducing the strongest immune responses at 1 month post-vaccination (T1). At T1, the GMTs of neutralizing antibodies in both Covilo-S3 and CoronaVac-S3 were markedly higher than those in S1 and S2, with GMTs reaching 57.2 and 59.4, respectively-findings that support the notion that an extended interval between the second and third doses enhances the magnitude of the antibody response. Consistent with our findings, a study from Taiwan demonstrated that a fourth dose elicited anti-spike IgG titers 1.33-fold higher than peak levels after the third dose, further supporting that additional vaccine doses enhance humoral immunity in this population (31). A slight difference was observed in the S1 schedule, where CoronaVac induced a higher neutralizing antibody GMT (21.8) than Covilo (15.4), suggesting minor variations in the primary immune response of the two inactivated vaccines in the elderly. While neutralizing antibody titers declined progressively over the 12-month follow-up, the S3 schedule maintained the highest GMTs in both vaccine groups, with Covilo-S3 at 9.9 and CoronaVac-S3 at 10.0 at T4. Additionally, CoronaVac-S2 outperformed Covilo-S2 at T4 (8.0 vs. 5.1), indicating that vaccine-specific immune persistence differs even under the same dosing schedule. The dynamics of SARS-CoV-2-specific IgG antibodies (anti-S1+NP and anti-RBD) mirrored the neutralizing antibody results: the S3 schedule yielded the highest geometric mean concentrations (GMCs) at T1, with CoronaVac-S3 showing marginally higher anti-S1+NP IgG levels than Covilo-S3. For anti-RBD IgG, CoronaVac’s S2 and S3 schedules had significantly higher GMCs than S1, highlighting that a third booster dose is critical for inducing robust antibody responses against the receptor-binding domain-a key target for SARS-CoV-2 neutralization.

In terms of antibody responses against SARS-CoV-2 Delta and Omicron Variants, our pseudovirus-based neutralization assays revealed that the S3 schedule conferred the strongest inhibition of the wild-type (WT) SARS-CoV-2 strain and Delta variant at T1, with Covilo-S2 and S3 exhibiting superior inhibition compared to their CoronaVac counterparts for both variants. This is in line with a Hong Kong study that reported third-dose booster vaccination significantly enhanced neutralization activity against the ancestral strain and Delta variant in older adults (32). A third mRNA booster after two ChAdOx1-S doses significantly enhances neutralization against SARS-CoV-2 variants, according to a Taiwanese study on healthcare workers (33). A third dose of mRNA vaccine significantly boosts antibody responses in older care home residents and, for the first time, effectively elicits neutralizing capacity against the Omicron variant. Although antibody levels decline rapidly, T-cell cross-recognition remains well-preserved, highlighting its critical role in protecting older adults against immune-evasive variants (34). A study from Canada shows that a third dose of an mRNA vaccine significantly enhances humoral immune responses in older adults, bringing their antibody levels, functional activity, and neutralizing capacity against the Omicron variant to levels comparable to those observed in younger individuals (35). A study from Taiwan demonstrated that a fourth dose of mRNA vaccine significantly increased neutralizing activity against the D614G variant in older adults, with fold-rises ranging from 2.76 to 4.07; however, neutralization titers against the XBB.1.16 subvariant were 17- to 29-fold lower than those against D614G, highlighting the immune evasive nature of emerging Omicron sublineages (31). Although multiple real-world studies have shown that antibody levels gradually decline over time, inactivated vaccines can still maintain durable protection against severe disease, highlighting the role of immune memory (36–38).

Notably, all vaccination groups showed weakest inhibition of the Omicron variant at T1, a finding consistent with global research on inactivated COVID-19 vaccines. Omicron’s extensive mutations in the spike protein, particularly in the RBD region, enable it to evade neutralizing antibodies induced by vaccines targeting the ancestral strain, which explains the lack of effective neutralization observed in our study (39). The hierarchical inhibition of WT > Delta > Omicron across all groups further underscores the impact of viral evolution on the protective efficacy of first-generation inactivated vaccines, and the need for updated vaccines targeting circulating variants for this population (40).

Our clinical outcome data showed that the S2 and S3 schedule was associated with the lowest incidence of long COVID among recipients, with S1 having the highest rates-14.9% for long COVID in S1 compared to 31.9% in S2 and 28.4% in S3. Muscular soreness and runny nose were the most significantly different symptoms across schedules, with higher rates in S1, while the duration of symptom recovery did not differ notably. Multivariate logistic regression analysis identified male sex as a protective factor against COVID-19 infection rates and long COVID, with an odds ratio of 0.5 and 0.3, which is consistent with several international cohort studies reporting gender differences in COVID-19 clinical outcomes, possibly due to biological and immunological differences between males and females. Our findings also align with a large-scale study across the UK, Spain and Estonia that confirmed COVID-19 vaccination reduces the risk of long COVID, and extend this evidence by showing that optimized booster intervals further lower this risk in older adults (41). However, it is important to note that while booster vaccination reduced symptom severity and long COVID risk, it did not eliminate breakthrough infections-likely due to the widespread circulation of the Omicron variant during the study’s follow-up period, which evades vaccine-induced immunity, as reported in a Hong Kong study that found limited protection of CoronaVac and BNT162b2 boosters against Omicron infection in older adults (42).

This study has several notable limitations that should be acknowledged when interpreting its findings. First, our assessments of SARS-CoV-2 neutralizing activity were primarily centered on the ancestral strain and Delta variant, with extremely limited testing of the Omicron variant and its sublineages; as Omicron had become the dominant circulating strain during the study’s follow-up period, this gap weakens the clinical relevance of our results for the current COVID-19 epidemic landscape and prevents clear conclusions about the booster’s protective efficacy against this prevalent variant. Second, the research only quantified humoral immunity-related indices, such as neutralizing antibody titers and SARS-CoV-2-specific IgG levels, and did not evaluate cell-mediated immunity-an essential component of long-term immune protection induced by COVID-19 vaccines. The lack of cellular immunity data means we cannot fully and comprehensively elucidate the overall immune protection mechanism of inactivated COVID-19 vaccines in the elderly population. Third, while this was a prospective cohort study, local adjustments to COVID-19 vaccination policies during the long-term follow-up led to a certain rate of participant loss to follow-up; in addition, the inherent observational nature of the study design introduced potential confounding factors, including unaccounted differences in participants’ underlying chronic diseases and individual baseline immune status, which may have interfered with the accuracy of our study outcomes. Fourth, all study participants were recruited from elderly populations in Zhejiang Province, China, resulting in obvious geographical restriction; meanwhile, the age range of the subjects was limited to 60–80 years, with no inclusion of the oldest-old population over 80 years old.

In conclusion, our study demonstrates that a third booster dose of either inactivated vaccine significantly enhances immune responses in adults aged 60 years and older, particularly when administered 2–6 months after the second dose. This booster induces substantial increases in neutralizing antibody levels, thereby improving immune protection against SARS-CoV-2 and its variants; it also effectively reduces the symptoms, severity, and duration of COVID-19 infection, highlighting the critical role of vaccination in preventing long COVID.

The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the National Natural Science Foundation of China (82302519); the key grants of Department of Science and Technology of Zhejiang Province (2024C03216,2025C02186); the Key Program of Health Commission of Zhejiang Province/Science Foundation of National Health Commission (WKJ-ZJ-2523); the National Key Research and Development Project by the Ministry of Science and the Technology of China (2023YFC2308705); the Zhejiang Provincial Medical and Health Science and Technology Plan (2023RC143); the Zhejiang Provincial Disease Prevention and Control Science and Technology Plan (2025JK014); the Disease Prevention and Control Innovation Team of Zhejiang Province (2026JKC-04); the Young Talent Support Program of Zhejiang Provincial Association for Science and Technology; the Young Emerging Talents in Medicine of Zhejiang Province; the Advanced Training Program for Young Elites in Public Health of the Chinese Preventive Medicine Association.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

The study protocol and informed consent form were approved by the Medical Ethics Committee of The Zhejiang Center for Disease Control and Prevention (2021-044-01). Written informed consent was obtained from all study participants. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Ethical approval was not required for the studies on animals in accordance with the local legislation and institutional requirements because only commercially available established cell lines were used. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

RD: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. QH: Conceptualization, Data curation, Investigation, Methodology, Software, Supervision, Writing – review & editing. XL: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – review & editing. LM: Data curation, Formal analysis, Methodology, Project administration, Supervision, Validation, Writing – review & editing. RB: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Writing – review & editing. HL: Funding acquisition, Investigation, Resources, Software, Writing – review & editing. PY: Data curation, Formal analysis, Funding acquisition, Project administration, Resources, Writing – review & editing. YL: Project administration, Resources, Supervision, Validation, Visualization, Writing – review & editing. JY: Data curation, Formal analysis, Writing – review & editing. SH: Formal analysis, Supervision, Visualization, Conceptualization, Investigation, Software, Writing – review & editing. JJ: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Software, Supervision, Validation, Writing – review & editing. HZ: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author(s) declared that generative AI was used in the creation of this manuscript. Generative AI was used only for language editing purposes to enhance the clarity and readability of the manuscript.

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