Tuberculosis following two-dose SARS-CoV-2 vaccination with messenger RNA vaccine (BNT162b2) and inactivated virus vaccine (CoronaVac)

Dear editor,

Although the waning of antibodies is anticipated after two-dose SARS-CoV-2 vaccination, the cellular response, especially the Th1 cell response that promotes T-cell immunity, has been reported recently.¹ Development of the T-cell and cellular immune response triggers long-term memory with potential cross-pathogen protection – known as trained immunity.^{2 , 3} Animal and epidemiological studies4, 5, 6 showed a cross-protection effect from Bacille Calmette-Guerin (BCG) vaccination on COVID-19 by inducing trained immunity. We hypothesize that SARS-CoV-2 vaccination could also trigger trained immunity and offer protection against tuberculosis (TB) through a similar mechanism.

In this population-based real-world outcome study in Hong Kong, we linked territory-wide electronic health records (EHRs) with SARS-CoV-2 vaccination records and applied two epidemiological study designs, case-control study and retrospective cohort study, to investigate the effect of two-dose SARS-CoV-2 vaccination on the occurrence of TB. Matching between EHR and vaccination records was based on anonymized personal identification document numbers. The record-linked EHR database has been used for several population-based pharmacovigilance studies for the SARS-CoV-2 vaccine with proven population representativeness and data accuracy.^{7 , 8}

We identified the interest of outcome as newly diagnosed TB from the inpatient setting between February 23, 2021, and January 31, 2022, using ICD-9-CM diagnostic codes (010–018). To ensure the TB cases were incident events during the period, patients with a recorded TB diagnosis or TB-related antibiotics prescription (isoniazid or rifampin) were excluded. Cases were further verified by prescription records of isoniazid, rifampin, pyrazinamide and ethambutol or streptomycin within 14 days after hospital admission. In the cohort study, we included all the patients’ records in the linked database and categorized the cohort into two-dose vaccinated or unvaccinated group according to the vaccination status by September 30, 2021. We matched vaccine recipients with unvaccinated individuals by age and sex using maximum ratio matching and followed them up until the occurrence of outcome, death or study end date. Patients with metastatic cancer, age<18 years, with clinical history of TB or TB-related treatment, or with single-dose or heterologous vaccines were excluded. Multi-group Inverse Probability of Treatment Weighting (IPTW) was adopted to ascertain the balance of patient characteristics across groups. Cox Proportional-Hazards model was applied to estimate the hazard ratio (HR). In the nested case-control study, TB cases were 1:10 matched with controls admitted to hospital during the same period but without a diagnosis of TB, using the incidence density sampling with replacement by age, sex, and hospital admission date (±1 day). Multivariable conditional logistic regression was applied to evaluate odds ratio (OR). HR and OR were estimated separately for BNT162b2 and CoronaVac. Subgroup analysis (by age, sex) and a series of sensitivity analyses were conducted. The detailed study design and statistical analysis are shown in Supplementary Methods.

The study cohort included 1662,879 unvaccinated individuals, 1320,654 two-dose BNT162b2 vaccine recipients, and 944,331 two-dose CoronaVac vaccine recipients (Supplementary Fig. 1). After IPTW with 1% extreme values trimmed, we obtained a well-balanced cohort with all standard mean difference (SMD) <0.1 except for age (Supplementary Table 1), which was adjusted by Cox regression. During a median follow-up of 178–199 days, incidence of TB in the BNT162b2 group [(1.35 (95% CI: 1.1–1.63) per 10,000-person year] and the CoronaVac group [1.53 (95% CI: 1.23–1.89) per 10,000-person year] were lower than the unvaccinated group [3.47 (95% CI: 3.09–3.88) per 10,000-person year] (Supplementary Table 2). Cox regression showed the adjusted HR was 0.42 (95% CI: 0.31–0.57) for BNT162b2 and 0.51 (95% CI: 0.39- 0.69) for CoronaVac when compared to the unvaccinated group. Age- and sex-stratified Cox regression showed similar associations for both vaccines (Fig. 1 ). Sensitivity analyses using the recorded diagnosis of TB regardless of TB-related prescription as the outcome definition, considering 30 days washout period for TB occurrence, Fine-Gray regression considering death as a competing risk for TB, or using appendicitis as the negative outcome control, all showed similar findings with the main analysis (Table 1 ). The case-control study (Supplementary Fig. 2 for cases and controls selection and Supplementary Table 3 for baseline demographics) yielded similar, but a more conservative risk estimate [adjusted OR 0.76 (95% CI: 0.57–1.01) for BNT162b2; 0.74 (95% CI: 0.56–0.99) for CoronaVac] (Fig. 1).

Fig. 1.

Risk estimation from cohort and case-control study.

Table 1.

Sensitivity analyses for cohort study.

	Events (N)	Cohorts (N)	Time-to-event [days, median (IQR)]	Follow-up time (person-years)	Incidence (10,000 person-years, 95% CI)	Adjusted HR (95% CI)	P-value
Hospitalized TB regardless of TB-related prescription within 14 days
None	554	1,662,879	178 (144, 226)	849,496	6.52(5.99, 7.08)	Ref
BNT162b2	131	1,320,654	188 (158, 230)	712,629.8	1.84(1.54, 2.17)	0.36 (0.27, 0.47)	<0.001
CoronaVac	130	944,331	199 (164, 255)	541,118	2.4(2.01, 2.84)	0.45 (0.36, 0.57)	<0.001
30-day wash out period for TB definition
None	250	1,662,879	178 (144, 226)	849,587.4	2.94(2.59, 3.32)	Ref
BNT162b2	88	1,320,654	188 (158, 230)	712,641.8	1.23(0.99, 1.51)	0.44 (0.32, 0.6)	<0.001
CoronaVac	76	944,331	199 (164, 255)	541,134.3	1.4(1.11, 1.74)	0.54 (0.4, 0.74)	<0.001
Fine-Gray competing risk of death analysis
None	295	1,662,879	178 (144, 226)	849,565.4	3.47(3.09, 3.88)	Ref
BNT162b2	96	1,320,654	188 (158, 230)	712,638.1	1.35(1.1, 1.63)	0.49 (0.38, 0.62)	<0.001
CoronaVac	83	944,331	199 (164, 255)	541,130.4	1.53(1.23, 1.89)	0.51 (0.4, 0.66)	<0.001
Negative outcome control (appendicitis)
None	468	1,662,879	178 (144, 226)	849,519.7	5.51(5.02, 6.02)	Ref
BNT162b2	495	1,320,654	188 (158, 230)	712,514.6	6.95(6.35, 7.58)	1.10 (0.94, 1.29)	0.222
CoronaVac	328	944,331	199 (164, 255)	541,041.6	6.06(5.43, 6.74)	1.01 (0.87, 1.18)	0.859

Hong Kong is among the few jurisdictions that implemented two types of SARS-CoV-2 vaccines with established territory-wide vaccine safety surveillance. From both mRNA and inactivated virus vaccine technology platforms, we observed a significantly lower risk of incident TB among people who received two-dose vaccines. The overall estimated relative risk reduction was 49–58% in the cohort analysis and 24–26% in the case-control analysis. Consistent findings from sensitivity analyses further supports the trained immunity theory, and it is likely that the cross-pathogen protection could be sustained for at least 6 months, according to the median follow-up period of the cohort study.

Long-term boosting of innate immune responses by live vaccines, such as BCG, could potentially induce heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells.⁹ Therefore, it was proposed that the induction of trained immunity might represent an important tool for reducing susceptibility to and severity of SARS-CoV-2,⁹ which was recently proved in an animal study with SARS-CoV-2 challenge.⁶ Our results, consistent with the trained immunity theory, warrants further pathogenesis and epigenetic investigation. Notably, our observation relating to the cross-pathogen protection is not specific to mRNA or inactivated virus vaccine platform. This indicates that the trained immunity might involve several cell-pathogenesis cross-talks and regulations, and the potential of whole-microorganism vaccines as an important tool for reducing the susceptibility of SARS-CoV-2.

Despite several limitations inherently associated with EHR-based real-world outcome studies, our study has significant public health implications, particularly for low-and low-middle-income economies with dual threats from high prevalent TB and uncontrolled COVID-19 due to low uptake of SARS-CoV-2 vaccines.¹⁰ Potential additional benefits of SARS-CoV-2 vaccination should be made known to the public to overcome vaccine hesitancy; and to policymakers, to facilitate feasible and cost-effective vaccination programs for COVID-19 and TB control.

Ethics approval

This study was approved by the Institutional Review Board of the University of Hong Kong / Hospital Authority Hong Kong West (UW 21–149 and UW 21–138) and the Department of Health Ethics Committee (LM 21/2021).

Data availability

Data are not available as the data custodians (the Hospital Authority and the Department of Health of Hong Kong SAR) have not given permission for sharing due to patient confidentiality and privacy concerns. Local academic institutions, government departments, or non-governmental organizations may apply for access to data through the Hospital Authority's data sharing portal (https://www3.ha.org.hk/data).

Author's contribution

Professor Wong had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: XL, KP, ICKW

Drafting of the manuscript: XL, KP

Data acquisition and management: CSLC, FTTL, EYFW, XL, CKW, EWC, ICKW

Statistical analysis: KP, FC, XL

Clinical investigators: DCLL, MSMI, CSL

Interpretation of data: all authors

Critical revision of the manuscript for important intellectual content: all authors

Administrative, technical, or material support: ICKW, EWC

Supervision: XL, ICKW

Funding

Food and Health Bureau, the Government of the Hong Kong Special Administrative Region (Ref: COVID19F01).

Declaration of Competing Interest

XL received research grants from Research Fund Secretariat of the Food and Health Bureau (HMRF, HKSAR), Research Grants Council Early Career Scheme (RGC/ECS, HKSAR), Janssen and Pfizer; internal funding from the University of Hong Kong; consultancy fee from Merck Sharp & Dohme and Pfizer, unrelated to this work. EYFW has received research grants from the Food and Health Bureau of the Government of the Hong Kong SAR, and the Hong Kong Research Grants Council, outside the submitted work. FTTL has been supported by the RGC Postdoctoral Fellowship under the Hong Kong Research Grants Council and has received research grants from Food and Health Bureau of the Government of the Hong Kong SAR, outside the submitted work. CKHW reports receipt of research funding from the EuroQoL Group Research Foundation, the Hong Kong Research Grants Council, and the Hong Kong Health and Medical Research Fund; all of which are outside this work. EWC reports grants from Research Grants Council (RGC, Hong Kong), Research Fund Secretariat of the Food and Health Bureau, National Natural Science Fund of China, Wellcome Trust, Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Amgen, Takeda, Narcotics Division of the Security Bureau of HKSAR; honorarium from Hospital Authority, outside the submitted work. KKL received grants from the Research Fund Secretariat of the Food and Health Bureau, Innovation and Technology Bureau, Research Grants Council, Amgen, Boehringer Ingelheim, Eisai and Pfizer; and consultation fees from Amgen, Boehringer Ingelheim, Daiichi Sankyo and Sanofi, all outside the submitted work. CSLC has received grants from the Food and Health Bureau of the Hong Kong Government, Hong Kong Research Grant Council, Hong Kong Innovation and Technology Commission, Pfizer, IQVIA, and Amgen; personal fees from Primevigilance Ltd.; outside the submitted work. ICKW reports research funding outside the submitted work from Amgen, Bristol-Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, the Hong Kong RGC, and the Hong Kong Health and Medical Research Fund, National Institute for Health Research in England, European Commission, National Health and Medical Research Council in Australia, and also received speaker fees from Janssen and Medice in the previous 3 years. He is also an independent non-executive director of Jacobson Medical in Hong Kong. The other authors declared no conflict of interest.