Maintenance of Long-Term Effective Humoral Immune Response in Patients with COVID-19 with Homologous or Heterologous Booster Vaccines: A Retrospective Study

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and first identified in Wuhan, China, in December 2019, has led to global efforts in vaccination to mitigate rising morbidity and mortality, with vaccines proving crucial in controlling the pandemic. This study evaluated the humoral responses to the inactivated virus vaccine Sinopharm or Koxing Kerlafor, the protein subunit vaccine ZF001, and the adenoviral vector vaccine Convidecia after 18 months of inactivated virus vaccination by heterologous and homologous booster vaccination in patients with previous SARS-CoV-2 infection and healthy individuals. We discovered that patients who had recovered from the infection and then received a third vaccine dose (booster) exhibited durable immunity. Furthermore, the heterologous booster vaccine induced higher neutralizing antibody responses compared with the homologous booster. These findings offer valuable insights into the efficacy of different COVID-19 vaccine strategies following booster immunization.

Introduction

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first emerged in Wuhan, China, in December 2019 and subsequently spread globally (Yu et al., 2022; Zhao et al., 2021). With morbidity and mortality from COVID-19 on the rise, vaccination is one of the safest ways to control pandemics and restore global health.

Since the first COVID-19 vaccinations were administered in late 2020, the Omicron outbreak in Shanghai in March 2022, which infected 630,000 people, underscored the need to update the COVID-19 vaccine (Mallapaty, 2021; Zhang et al., 2022). Currently, three main types of vaccines are available in China: inactivated vaccines, recombinant protein subunit vaccines, and adenovirus vector vaccines (Jin et al., 2022). Among these, the inactivated vaccine has been shown to induce lower levels of antibodies, whereas the recombinant protein subunit and adjuvanted vector vaccines have induced higher levels (Earle et al., 2021). ZF2001 is a protein subunit vaccine that uses a tandemly repeated SARS-CoV-2 spike receptor binding domain (RBD) dimer as the antigen (Zhao et al., 2021). ZF2001 has demonstrated efficacy and safety in Phase 3 clinical trials (Eybpoosh et al., 2023; Yang et al., 2021). In March 2001, ZF2001 was approved for emergency use in China and Uzbekistan and is currently administered as a three-dose vaccine (Zhao et al., 2021). Studies have demonstrated that a three-dose regimen of the inactivated vaccine significantly enhances protection against severe disease. Gao et al. reported that repeated administration of the inactivated vaccine may trigger a strong immune response to the original virus strain, potentially inhibiting the response to new strains (Gao et al., 2023). Real-world data suggest that the three-dose inactivated vaccine regimen is 78.8% effective against asymptomatic COVID-19, whereas a heterologous booster shows an effectiveness of 93.2–96.5% (Jara et al., 2022). Further research indicates that heterologous boosters not only generate stronger immune responses but also provide greater protection compared to homologous boosters, pointing to potential strategic improvements in vaccine efficacy (Costa Clemens et al., 2022).

Here, we analyzed the antibody levels of 208 patients with COVID-19 during hospitalization and after recovery. These patients received homologous inactivated vaccines, heterologous recombinant subunit vaccines (ZF2001), or adenovirus vector vaccines (Convidecia). Heterologous booster vaccines induced higher levels of humoral immune responses compared with homologous booster vaccines, and patients vaccinated with a third dose of vaccine (booster) after recovery resulted in durable immunity. In conclusion, our findings highlight the importance of heterologous vaccination and provide guidance for novel vaccination strategies.

Materials and Methods

Subjects

Sample source

This study retrospectively collected data from 208 patients with COVID-19 hospitalized at Shijiazhuang No. 5 Hospital from January 5 to April 6, 2021. The target population consisted of individuals aged 18 years or older who tested positive for SARS-CoV-2 nucleic acid by reverse transcription polymerase chain reaction; individuals who tested negative for SARS-CoV-2, malignant tumors, or immunodeficiency diseases were excluded from the study. In addition, 50 healthy individuals served as controls (Table 1; Supplementary Table S1), and the healthy controls were matched to the patients for age and sex.

Table 1.

The Demographic Characteristics of All COVID-19 Cases

Characteristic	COVID-19 n = 208	Healthy control n = 50	p-Value
Vaccine
Inactivated vaccine	62 (29.8%)	27 (54%)	0.001^b
Recombinant subunit vaccine	104 (50.0%)	11 (22%)
Adenovirus vector vaccine	42 (20.2%)	12 (24%)
Gender
Male	69 (33.2%)	23 (65.7%)	0.001^b
Female	139 (66.8%)	12 (34.3%)
Age
Mean (SD)	56.6 (12.9)	53.5 (11.0)	0.033^a
45–64	107 (51.4%)	33 (66%)	0.057^b
≥65	69 (33.3%)	8 (16%)
COVID-19 typing
Asymptomatic	31 (14.9%)
Mild	5 (2.4%)
Moderate	159 (76.4%)
Severe/critical	13 (6.3%)
Disease
Without chronic disease	127 (61.1%)
With chronic disease	81 (38.9%)

One-way ANOVA test.

Chi-square test.

A p-value <0.05 was considered significant.

ANOVA, analysis of variance; SD, standard deviation.

Sample collection

All patients with COVID-19 and healthy controls received the first dose of inactivated COVID-19 vaccine (Sinopharm or Koxing Kerlafor) in August 2021, followed by a second dose of live vaccine 20–30 days later. All participants received a booster vaccine (inactivated/recombinant subunit vaccine [ZF2001, Anhui Zhifei Longkang Biopharmaceuticals]/adenovirus vector vaccine [Convidecia, Concinia Biologics]) 6–7 months later, with vaccination ending in March 2022. Blood samples of 5 mL were collected from patients with COVID-19 at 1 week to 8 weeks and at 3 months, and 5 mL were collected from patients with COVID-19 and healthy controls at 18 months (V3 + 4M: third booster vaccination + change in antibody levels 4 months after vaccination) (Fig. 1A).

FIG. 1.

Timeline of COVID-19 infection, vaccination, sample collection, and changes in IgM antibody levels and experimental methods. (A) Chronological overview of COVID-19 infections, vaccinations, and testing procedures, along with the associated experimental approaches. Beginning in August 2021, patients with COVID-19 and healthy controls received the first dose of inactivated COVID-19 vaccine (Sinopharm or Koxing Colafer) after recovery and discharge from the hospital and the second dose of inactivated vaccine 20–30 days later. All participants received a booster vaccine (inactivated vaccine/recombinant subunit vaccine [ZF2001, Anhui Zhifeilongkang Biopharmaceutical]/adenovirus vector vaccine [Convidecia, Concinol Biologics]) 6–7 months later, and the vaccination ended in March 2022, and blood samples were collected on July 14, 2022, at 18 months (V3 + 4M), and the collected blood samples were tested for antibodies by chemiluminescence for antibody detection and data analysis. (B) Changes in anti-SARS-CoV-2 IgM levels from week 1 to 3 months after diagnosis and comparison of IgM at 18 months after booster vaccination with that at week 5 of infection and 3 months after recovery. The x-axis represents days since diagnosis, W denotes weeks, M denotes months, and n denotes sample size, and the y-axis represents antibody level. IgM, immunoglobulin M.

Sample grouping

Participants were classified according to the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 8) (China NHC of the PR of and Medicine NA of TC, 2022). Asymptomatic cases were defined as those with a positive SARS-CoV-2 test and no clinically identifiable or self-reported symptoms. Mild cases were defined as patients with mild clinical symptoms and no imaging evidence of pneumonia. Moderate patients with COVID-19 have fever and respiratory symptoms with imaging evidence of pneumonia.

Severe patients must meet the following criteria: shortness of breath, respiratory rate ≥30/min, oxygen saturation ≤93% at rest, partial pressure of arterial oxygen/inspired oxygen fraction ≤300 mm Hg, and lung imaging showing more than 50% progression of the lesion within 24–48 h. Critical care cases were defined as respiratory failure requiring mechanical ventilation for shock. The cohort included 31 asymptomatic patients, 5 mild cases, 159 moderate cases, and 13 patients with severe or critical disease. Subjects’ comorbidities included hypertension, diabetes mellitus, coronary artery disease, cerebrovascular disease, chronic kidney disease, chronic liver disease, and chronic lung disease.

Chemiluminescence immunoassay

Anti-SARS-CoV-2 immunoglobulin M (IgM), IgA, IgG, and Neutralizing Antibody （NAb） antibodies targeting the nucleoprotein, spike protein, and RBDs were detected using a chemiluminescence immunoassay kit (iFlash 2019-nCoV YHLO Biotech Co., Ltd., Shenzhen, China). The assay uses a paramagnetic particle-based chemiluminescence immunoassay to detect antibodies. SARS-CoV-2 magnetic beads containing antigen-coated SARS-CoV-2 bind to serum samples to form a complex, and then acridinium ester-labeled angiotensin-converting enzyme-2 coupler is added to compete with the particles for binding to form another reaction mixture. The iFlash3000-A chemiluminescence immunoassay analyzer (YHLO Biotech Co., Ltd.) converts the relative light units (RLU) detected into antibody titers (AU/mL) using a two-point calibration curve. The SARS-CoV-2 NAb levels in the sample were inversely proportional to the RLU detected by the iFlash optical system. Titers ≥10.0 AU/mL were considered positive (or reactive) for IgM, IgA, IgG, and NAb according to the manufacturer. Total IgM was assayed in 553 serum specimens from 208 patients, S1-IgG in 636 serum specimens from 208 patients, IgA in 323 serum specimens from 121 patients, and NAb in 498 serum specimens from 208 patients. One to five assays were performed on patients.

Statistical analysis

All data were statistically analyzed using SPSS 25.0. For normally distributed data, results were expressed as mean ± standard deviation (SD), and a t-test was used. For non-normally distributed data, all results were expressed as median (interquartile range), and the Wilcoxon rank sum test was used. When multiple datasets were analyzed, the Kruskal–Wallis test with post hoc Bonferroni correction was used due to the non-normal distribution of multiple values. One-way analysis of variance and chi-squared tests were used to evaluate variables such as age, gender, and type of vaccination. The hypothesis was tested using a two-tailed test, and p < 0.05 was considered statistically significant.

Results

Study population

A total of 258 participants, including 208 patients diagnosed with COVID-19 and 50 healthy controls, were enrolled in this study. The mean age of all patients was 56.6 ± 12.9 years, with 38.9% of patients with chronic diseases and 61.1% of patients without chronic diseases. In total, 33.2% of the patients were male while 66.8% were female. In total, 14.9% of patients were diagnosed as asymptomatically infected, 2.4% were diagnosed as mild, 76.4% were diagnosed as moderate, and 6.3% were diagnosed as severe or critical. There were significant differences between the experimental and control groups in terms of gender or vaccination (p < 0.05). The data of all patients are summarized in Table 1; Supplementary Table S1. All participants received the third booster vaccine in March 2022, and 29.8%, 50.0%, and 20.2% of patients received inactivated vaccine, ZF2001 vaccine, and adenovirus vector vaccine as booster vaccines, respectively. In the healthy control group, 27, 11, and 12 patients received inactivated vaccine, ZF2001 vaccine, and adenovirus vector vaccine as booster vaccines. We collected blood samples from patients with COVID-19 from 1 week to 8 weeks and 3 months, and V3 + 4M, and the collected blood samples were analyzed for changes in the levels of IgM, S1 protein IgG (S1-IgG), IgA, and Nab antibodies (Fig. 1A).

Dynamic analysis of post-infection and post-vaccination immune responses to anti-SARS-CoV—2 IgM, IgA, IgG, and NAb antibodies

To characterize the dynamics of humoral immunity after SARS-CoV-2 infection and after convalescent vaccination, we compared the levels of IgM, S1-IgG, IgA, and Nab antibodies in patients over an 18-month period to assess the effectiveness of booster vaccines.

During the patient’s infection, antibody levels of IgM, S1-IgG, and IgA were relatively low in week 1 and increased to a peak in week 5, with antibody positivity rates of 16.9%, 19.8%, and 4.6%, respectively, but the IgM positivity rate did not reach 100%, with a maximum of 90.9% in month 3. The positivity rate of S1-IgG in the later part of the hospitalization and during the follow-up period was 100%, and the IgA positivity rate reached 100% at week 7 and remained at 90.2% during the follow-up period. Positivity reached 100% and remained at 90.2% during the follow-up period (Figs. 1B and 2A, B). NAb antibody levels increased to a peak at week 3, with positivity rates approaching 100% in the later part of the hospitalization and during the follow-up period (Fig. 2C). After patients recovered from vaccination, S1-IgG and IgA levels increased significantly (p < 0.001) and were higher than the peak antibody levels at week 5 during hospitalization, and NAb levels returned to the same levels as during hospitalization. The results suggest a significant effect of booster vaccination after patient recovery.

FIG. 2.

Temporal dynamic changes of anti-SARS-CoV-2 antibodies. (A) Changes in anti-SARS-CoV-2 S1-IgG levels from week 1 to 3 months after diagnosis and comparison of IgM at 18 months after booster vaccination with that at week 5 of infection and 3 months after recovery. (B) Changes in anti-SARS-CoV-2 IgA levels from week 1 to 7 after diagnosis and comparison of IgA at 18 months after booster vaccination with that at week 5 of infection and week 7 after recovery. (C) Changes in anti-SARS-CoV-2 Nab levels from week 1 to 7 after diagnosis and comparison of NAb at 18 months after booster vaccination with that at week 5 of infection and week 7 after recovery. The x-axis indicates a few weeks since diagnosis, W denotes weeks, M denotes months, and n denotes sample size, and the y-axis indicates the antibody level in patients with confirmed COVID-19.

Comparison of antibody persistence with homologous or heterologous booster vaccines in patients with COVID-19 and healthy controls

To assess differences in antibody persistence with homologous or heterologous booster vaccines, we examined post-booster antibody levels in patients and healthy controls. S1-IgG and NAb levels were significantly higher in patients with COVID-19 after booster vaccination (p < 0.001) and were significantly higher in patients with moderate and severe/critical forms than in patients with asymptomatic forms (Fig. 3A). S1-IgG and NAb levels were significantly higher in patients vaccinated with recombinant subunit vaccines and adenovirus vector vaccines than in patients vaccinated with inactivated vaccines (p < 0.001). There was no significant difference in S1-IgG levels between the recombinant subunit vaccine and the adenovirus vector vaccine, but Nab levels were significantly higher in patients vaccinated with the ZF001 vaccine than in patients vaccinated with the adenovirus vector vaccine. In healthy controls, S1-IgG and NAb antibody levels were significantly higher in patients than in healthy controls, and there were no differences in antibody levels between those who received the recombinant subunit vaccine and those who received the inactivated vaccine, and antibody levels were higher in those who received the adenovirus vector vaccine than in those who received the inactivated vaccine (Fig. 3B).

FIG. 3.

Comparison of antibody levels between different groups at 18 months (V3 + 4M). (A) Comparison of S1-IgG and NAb levels between patients with COVID-19 of different severity and healthy controls. (B) Comparison of antibody levels between patients after different booster vaccinations. (C) Comparison of antibody levels after different booster vaccinations for males and females.

We also examined possible associations between homologous or heterologous boosting of vaccine-specific antibodies and demographic parameters such as age, gender, and chronic diseases. Regarding gender, S1-IgG and NAb antibody levels were significantly higher in females than in males after inactivated vaccination, and there was no significant difference between males and females vaccinated with recombinant subunit and adenoviral vector vaccines (Fig. 3C) (Supplementary Table S2). Regarding age, patients with COVID-19 were divided into three groups according to age: 18–44 years, 45–64 years, and ≥65 years. Among the three groups, S1-IgG and NAb concentrations were significantly higher in patients aged ≥65 years after inactivated vaccination than in patients aged 45–64 years (Supplementary Fig. S1A and Table S3), and there was no significant difference in antibody levels between patients in different age groups after recombinant subunit vaccine and adenovirus vector vaccine. With regard to chronic diseases, no differences were observed between patients with and without chronic diseases (Supplementary Fig. S1B and Table S4).

Discussion

We kinetically analyzed antibody levels, including IgM, S1-IgG, IgA, and NAb, in patients with COVID-19 for 18 months after disease onset. We found that the levels of IgG and NAb in severe patients were higher than those in non-severe patients, and those in moderate patients were higher than those in asymptomatic and healthy individuals. A number of studies have shown that disease severity may affect antibody levels (Guo et al., 2021; Wang et al., 2020). The reason may be that B-cell stimulation is stronger in severe patients, and plasma cells with a longer life span are generated (Amanna and Slifka, 2010). We also found that the antibody peaked at week 5, which is consistent with previous studies (Jiang et al., 2020). During natural infection, one study found that NAb levels in patients with COVID-19 can be maintained for 9 months (He et al., 2021). Our research extends the results of previous studies and adds vaccine factors. The positive rates and antibody levels of S1-IgG and Nab remained high until V3 + 4M. Bronsky et al. found that previous SARS-CoV-2 infections can increase immune status and antibody production after vaccination, and this mechanism was not interrupted in immunosuppressed individuals (Bronsky et al., 2023). The combination of the systemic immune response of naturally infected individuals and vaccination produced high levels of antibodies that persisted for a long time (Thon et al., 2023). Because of the half-life of antibodies, annual vaccination is recommended, especially in high-risk populations (Tworek et al., 2023).

Many studies have shown that heterologous booster immunization is an option to induce more effective and durable immunity (Cao et al., 2022; Eybpoosh et al., 2023; Kaabi et al., 2022; Zuo et al., 2022). Our results confirm and extend this finding that vaccination with a heterologous booster vaccine after natural infection has a higher protective effect. Consistent with our results, Wang et al. found that heterologous boosters of recombinant subunit vaccines induced NAb titers that were 3.5–6.8 times higher than those of homologous boosters and had a broader neutralizing capacity against mutant strains, including Omicron (Wang et al., 2022). Li et al. found that after two doses of inactivated vaccine using adenoviral vectored vaccines, the levels of NAb and cellular immune responses were significantly higher, and the immunogenicity was higher than that of the homologous booster vaccine (Li et al., 2022b). In addition, Ramezani et al. evaluated the humoral immune responses elicited by different protein subunit vaccines, PastoCovac and PastoCovac Plus, as booster vaccines in individuals who had been vaccinated with the BBIBP-CorV vaccine and found that the mean increase and fold increase in anti-RBD IgG and neutralizing antibodies were almost similar between booster vaccine recipients, with the heterologous regimen showing higher antibody titers compared to the BBIBP-CorV group. This is consistent with the results of the present study, which also found that NAb levels were significantly higher in patients vaccinated with the ZF001 recombinant subunit vaccine than in patients vaccinated with the adenoviral vector vaccine, suggesting that the recombinant subunit vaccine elicited a more robust humoral immune response (Farahmand et al., 2023; Ramezani et al., 2023). Overall, our study suggests that the heterologous booster vaccine appears to induce a stronger humoral immune response than the inactivated COVID-19 vaccine.

By analyzing different booster vaccines administered to patients with different demographic characteristics, we found that women had higher levels of inactivated vaccine antibodies than men. Several studies have shown that men have more severe COVID-19 outcomes (Fathi et al., 2021). One study showed that gender differences affect the immune response to the COVID-19 vaccine (Naaber et al., 2021); another study reported no significant difference in antibody titers between men and women after booster doses (Erdem et al., 2023). The exact cause of this sex difference is unknown, and further clinical trials are needed to identify and evaluate the impact of sex differences on COVID-19 vaccine efficacy. Our study also found that with respect to age, S1-IgG and NAb concentrations were significantly higher in patients aged ≥65 years after inactivated vaccination than in patients aged 45–64 years. Consistent with our findings, one study showed that two doses of inactivated coronavirus vaccine induced higher levels of neutralizing antibodies in elderly and cancer patients than in younger and healthy populations (Li et al., 2022a). In contrast, some studies have reported lower levels of SARS-CoV-2 antibodies in the elderly (Bruel et al., 2022; Meijide Míguez et al., 2023). Therefore, previous studies and the results of the present study suggest that the antibody response to SARS-CoV-2 was enhanced after a booster dose in the elderly, emphasizing the good immunogenicity of the booster dose in the elderly population.

Our study also has some shortcomings and limitations. Because it was a retrospective study, the sample sizes at weeks 7 and 8 were relatively small. Due to the sudden outbreak of the epidemic and the impact of prevention and control measures, the follow-up was not timely, and the antibody levels of patients after the first and second doses of vaccination were not tested. In particular, there is a need for further studies with large sample sizes. In addition, vaccination status was not assessed before vaccination. The follow-up period was short; therefore, long-term follow-up is needed to understand the duration of antibodies.

Conclusions

In conclusion, we evaluated and compared the humoral responses elicited by previously infected SARS-CoV-2 patients and healthy controls 18 months after the initial homologous regimen followed by a heterologous or homologous booster dose. We found that post-recovery patients vaccinated after the third vaccine dose (booster) achieved durable immunity and that immunization with the heterologous booster vaccine elicited higher neutralizing antibody responses than immunization with the homologous booster. These results provide important insights into the efficacy of different types of COVID-19 vaccines after booster immunization.

Footnotes

Acknowledgments

The authors thank all people who participated in the study.

Authors’ Contributions

X.Z. and L.L. read the literature related to the topic and participated in drafting the article. Y.L. and H.Z. revised the article. M.D. and K.Z. prepared figures. H.Y. and H.G. were responsible for conducting experiments and analyzing the data. J.L. and S.L. participated in searching literature. W.L. and Y.L. participated in document selection and supervision. A.F., E.D., and J.Z. participated in the design, revision, and final approval of the article. All authors contributed to the article and approved the submitted version.

Ethics Approval and Consent to Participate

The study was approved by the Medical Ethics Committee and the Medical Ethics Committee of the Fifth Hospital of Shijiazhuang City (ethics approval number: 2020008). Written informed consent was obtained from each patient.

Human and Animal Rights

All research studies on humans (individuals, samples, or data) have been performed in accordance with the principles stated in the Declaration of Helsinki.

Author Disclosure Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding Information

This work was supported by the Shijiazhuang Technology Support Plan (231200243) and the Key Research and Development Project of Hebei Province (22377744D).

Supplementary Material

Supplementary Figure S1

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

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