SARS-CoV-2 vaccination and semen quality: a study based on sperm donor candidate data in southwest China

Introduction

Numerous reports have indicated that sperm quality in men is declining at the population level (1-3). Non-genetic factors, such as environmental exposure and lifestyle, may be the most important factors contributing to the observed trends (4). Since December 2019, the global coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in high morbidity and mortality worldwide. It has affected social interaction, public health, and economics across the world (5). Vaccination against COVID-19 has become the most important method to reduce the COVID-19 morbidity and mortality burden (6). Consequently, the potential side effects from COVID-19 vaccines are of intense clinical, public health, and societal interests. Since the global sperm quality decline is of concern and male fertility plays a key role in human reproduction, the potential impact of SARS-CoV-2 vaccination on the male fertility is of particular interest.

Early studies have established that SARS-CoV-2 can impact on male reproductive system. Some scientific evidence has shown that COVID-19 infection can adversely affect testes and sperm quality (7-9), but other studies suggest that SARS-CoV-2 genetic material was rarely found in semen samples, with no observed viral transmission during sexual contact or assisted reproductive techniques (10-12). Recent bioinformatics evidence shows that the testis is a suspected target organ for SARS-CoV-2, and it is potentially vulnerable towards SARS-CoV-2 infection. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) have been shown to be highly expressed in spermatogonia and Sertoli and Leydig cells (13,14). Yet, SARS-CoV-2 infects host cells through ACE2 receptors, and TMPRSS2 plays a major role in SARS-CoV-2’s entry into cell (14). Furthermore, COVID-19 infection may cause testicular structure damage (7,13,15-17). According to histopathology and ultrastructural findings from COVID-19 fatalities, the SARS virus is prevalent in testicular tissue and causes testicular lesions by orchitis, vascular changes, basal membrane thickening, Leydig and Sertoli cell scarcity (13,16).

Because COVID-19 infection can result in serious illness and injury of multiple organs, and even deaths, developing vaccines against SARS-CoV-2 has been of utmost priority (18). The safety, efficacy, tolerability, and immunogenicity of these vaccines are emphasized in a number of clinical trials. To date, the majority of COVID-19 vaccines demonstrate relatively excellent efficacy based on published data of phase III clinical trials, and the risk of adverse events is acceptable (19,20). Nevertheless, although mass vaccination against SARS-CoV-2 has been authorized and implemented worldwide since 2020, their epidemiological impact on male fertility is not well understood, especially at the population level. A joint statement from the Society for Male Reproduction and Urology and the Society for the Study of Male Reproduction advises that COVID-19 vaccination should be offered to fertile men of reproductive age if they meet the vaccination criteria (https://connect.asrm.org/smru/forprofessionals/covid/new-page?ssopc=1). However, results from surveys conducted on couples preparing for pregnancy indicate that attitudes towards COVID-19 vaccination range from hesitant to refusal (21-25).

Vaccination has evolved into a routine and highly effective method for illness prevention during the COVID-19 pandemic. In China, at least three types of COVID-19 vaccines, which are inactivated SARS-CoV-2 vaccine, mRNA vaccine, and recombinant protein vaccines respectively, have received emergency-use approval (https://www.chinacdc.cn/jkzt/crb/zl/szkb_11803/jszl_12208/202103/t20210329_225214.html) based on their high efficacies and safety levels (26-31). The first type is an inactivated SARS-CoV-2 vaccine manufactured by Sinovac (PiCoVacc), the Beijing Institute of Biological Products (BBIBP-CorV), and the Wuhan Institute of Biological Products (Sinopharm-Wuhan inactivated vaccine). The second type is an mRNA vaccine manufactured by CanSinoBIO based on an adenovirus in partnership with the Chinese Academy of Military Medical Sciences. The third type, a recombinant new coronavirus vaccine [Chinese hamster ovary (CHO) cells, which are stably expressing SARS-CoV-2 spike protein], is produced by Zifivax using a protein to trigger an immune response (18). PiCoVacc9 and BBIBP-CorV10 are widely used, eliciting neutralizing antibodies (NAbs) in mice, rats, and non-human primates, with the nonhuman primates in the high-dose group being fully protected from infection by SARS-CoV-2 with no antibody-dependent enhancement (ADE) (18,32), while ADE has been observed in clinical cases (33,34). Evaluations of COVID-19 vaccine safety and efficacy have shown that vaccination can yield excellent efficacy against the original strain and some variants, while the risk of adverse events is acceptable (19,35-37). As of November 28, 2022, more than 3.44 billion vaccine doses had been provided freely for all people in China. China’s State Council stated that more than 1.34 billion people, or 92.54% of national population, had received two vaccine doses (http://www.gov.cn/xinwen/gwylflkjz216/index.htm).

In light of the long-term decreasing trend in human fertility and the ongoing COVID-19 pandemic, we examined the relationship between sperm quality and COVID-19 vaccination in China by analyzing data from a provincial sperm bank. To conduct this observational study, we recruited young adult men aged 20 to 45 years who applied to be sperm donors at Sichuan Human Sperm Bank of China, conducted survey to collect habitual information, and assessed sperm quality parameters before and after the administration of COVID-19 vaccination to understand the association between vaccination and sperm quality. This assessment is one of the first attempts to investigate the vaccination effect on male reproductive health using an epidemiological approach in China. We hope the findings could contribute to scientific knowledge about male reproductive health in the global pandemic era. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-23-395/rc).

Methods

Study population

To investigate the potential effect of COVID-19 vaccination on sperm quality in China, young adult men of age 20 to 45 years old who were sperm donor candidates at the Sichuan Human Sperm Bank of China were recruited between January 1, 2020 to December 31, 2021. And the sperm donor candidates, who have been ever infected with COVID-19, were excluded in the study. More information about Sichuan Human Sperm Bank of China and sperm donor recruitment could be obtained from previously published studies (38,39).

At the time of semen sample collection, the following demographic information was obtained through in-take survey: weight, height, age, education level, ethnicity, abstinence time, smoking and drinking history, residential address at the time of sample collection, and working address during study period. Information on SARS-CoV-2 vaccination (vaccination date, vaccination type, and dose number) and residential address at the time of sample collection was collected using self-reported electronic survey retrospectively.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Ethics approval for this study was obtained from the Institutional Review Board of West China Second University Hospital of Sichuan University (No. WCSUH-SCU IRB 2021-197), and individual consent for this retrospective analysis was waived.

Semen analysis

Semen collection and analysis followed the guidelines of World Health Organization (WHO) [2010]. In brief, semen samples were collected into a sterile container by masturbation. After collection, the sample was immediately incubated at 37 ℃ and evaluated directly. The volume of semen was obtained by weighing. Sperm concentration, motility, movement parameters were determined according to the WHO 2010 recommendations, measured by the Makler chamber and Computer Assisted Sperm Analysis (CASA) system [including sperm concentration (millions/mL), progressive sperm rate (%), average path velocity (VAP, µm/s), curvilinear velocity (VCL, µm/s), amplitude of lateral head displacement (ALH, µm/s), linearity (LIN, %), straight-line velocity (VSL, µm/s), beat-cross frequency (BCF, times/s), straightness (STR, %), and wobble (WOB, %)]. More information on semen analysis could be found in our earlier study (39).

Air pollution data and exposure assessment

To estimate person-specific exposure, we extracted each study individual’s residential address and converted the longitude and latitude to grid cells code at 0.01° resolution, then we matched the environmental data with the individual’s address grid. We created a grid with 0.01° resolution and then aligned the environmental data and the individuals’ addresses to the predefined grid. The daily full-coverage particulate matter (PM)_2.5 (µg/m³), PM₁₀ (µg/m³), O₃ (µg/m³), NO₂ (µg/m³), SO₂ (µg/m³), and CO (mg/m³) concentrations, as well as daily temperature (℃) and relative humidity (%) were estimated to match the address grids. Hourly raw meteorological data with a spatial resolution of 0.25° were obtained from the National Oceanic and Atmospheric Administration (NOAA, https://nomads.ncep.noaa.gov/). We resampled the temperature and relative humidity into 0.01° grid cells by using bilinear interpolation. We collected the hourly concentrations of six air pollutants from the China National Environmental Monitoring Centre (CNEMC, http://www.cnemc.cn/), including PM_2.5, PM₁₀, O₃, NO₂, SO₂, and CO. For satellite retrievals, we obtained the aerosol optical depth (AOD) data from the Himawari-8 and the Multi-Angle Implementation of Atmospheric Correction (MAIAC) products for estimating PM_2.5 and PM₁₀ (40,41). We also collected the tropospheric NO₂ columns and the total SO₂ (and O₃, CO) columns from the Sentinel-5P TROPOspheric Monitoring Instrument (TROPOMI) products to estimate the surface concentrations of gaseous pollutants (NO₂, SO₂, O₃, and CO) (40-42). Based on the air quality measurements, satellite retrievals, and various auxiliary variables such as meteorological conditions, population density, and land use types, we developed six separate machine learning models (i.e., extreme gradient boosting) to estimate the gridded concentrations of each air pollutant. The hourly estimations of six air pollutants, temperature, and relative humidity were then averaged to daily mean values. For details of the modeling process and prediction performance, please refer to the previous studies (42-44).

Statistical analysis

Two statistical models were constructed to analyze the potential association between vaccination and sperm quality. First, a generalized linear model examined whether vaccination (before or after vaccination) has significant association with each sperm quality parameter separately. The sperm quality parameters included indicators for semen characteristics (such as volume) and sperm motility (such as progressive rate). The model was adjusted for time between vaccination and semen sample collection, age, body mass index (BMI), education level, ethnicity, abstinence duration (days), drinking status (yes/no), smoking status (yes/no), 90-day average concentrations of air pollutants (PM_2.5, PM₁₀, O₃, SO₂, NO₂ and CO), 90-day average weather parameters (temperature and relative humidity) and vaccine manufacturer. Previous studies found statistically significant associations between the 90-day average pollutant concentrations and weather parameters with sperm quality parameters (38,39). Second, a mixed-effects model used the same aforementioned dependent, independent, and covariate variables as fixed affects, with individual identity document (ID) included as the random effect.

A subgroup analysis was conducted for semen samples that were collected between 60 and 90 days (inclusive) after first vaccination shot. The same two models (generalized linear and mixed effects) were constructed for this subgroup analysis, using the same model structure and variables. Sperm quality before and after vaccination was analyzed using two sample or pairwise t-test with significance level at 0.05.

Results

Based on sample selection criteria, a total of 2,955 semen samples collected from 564 individuals between January 1, 2020 to December 31, 2021 were included in our study. All study participants received at least one COVID-19 vaccine dose, and most (94.11%) received two doses. Out of the 564 individuals, 506 (89.72%) were vaccinated with an inactivated COVID-19 vaccine, while 10 (1.77%) and 7 (1.24%) were vaccinated with mRNA vaccine and recombinant new coronavirus vaccine (CHO cells), respectively (Table 1).

The study population was concentrated in metropolitan Chengdu, capital city of Sichuan Province, where there was higher pollution from particulates (PM_2.5 and PM₁₀), NO₂ CO, and O₃ during the study period (January 1, 2020 to December 31, 2021) compared to the surrounding regions (Figure 1). The study population was young, healthy (81.38% did not smoke and 61.17% did not drink) and with normal BMI (Table 1). They were overall highly-educated with 75.0% of individuals having a college education and approximately 14.54% having received graduate school education. Most of the study population was single and never married (86.88%). The sperm quality parameters from all sperm donor candidates before and after vaccination are summarized in Table 2 and Table S1. Based on analysis using all 2,955 semen samples, sperm motility parameters appeared to show statistical difference before and after the first vaccination (Table 2). And it was same to the results of before and after the second vaccination (Table S1). However, pair-wise comparison based on the 305 samples from the 71 individuals who donated before and after vaccination showed no statistical difference for any sperm quality parameters (Table 2, right column and Table S2).

Figure 1 Average pollutant concentrations across the study area and distribution of primary residence of study participants (January 1, 2020 to December 31, 2021).

Similarly, based on generalized linear model, semen samples collected before and after vaccination appeared to show statistically different concentration, progressive rate, total forward sperm, and motility (VCL, VAP, VSL, ALH) (Table S3). However, once individual ID was included in the mixed effects model, only VCL, VAP and VSL exhibited significant association ( P values are 0.04, 0.02 and 0.009, respectively) with vaccination (Table 3). ID (or individual) played the dominant role in variance contribution for semen volume (77%), sperm concentration (57%), progressive rate (58%), and for motility related parameters such as VCL (60%), VAP (56%), VSL (56%), STR (61%), ALH (53%) and BCF (56%). Interestingly, the time duration between semen sample collection and vaccination did not appear to have statistical association with sperm quality parameters (results not shown).

The characteristics of a sub-group of individuals who provided semen samples between 60 to 90 days post-vaccination were similar to the larger study population (Table S4) and the overall sperm quality was similar to that of the larger sample (Table S5). The lack of association between vaccination time and sperm quality parameters from mixed effects regression analysis on this subgroup with samples obtained 60–90 days (inclusive) after vaccination resembled that of the larger study population (Table S6).

Discussion

Our study examined the potential relationship between COVID-19 vaccination and sperm quality parameters. In this study, our results suggest that the Chinese COVID-19 vaccination is not statistically associated with changes in most sperm quality parameters except VCL, VSL and VAP, but rather variability between individuals appears to play the dominate role in contributing variance for these sperm quality parameters. The subgroup analysis on semen samples collected 60–90 days (inclusive) after vaccination showed no statistically significance at all.

To date, there are only a few studies reporting the potential relationship between COVID-19 vaccination and sperm quality. These study results indicated no significant decrease in sperm parameters after receiving the mRNA vaccine against SARS-CoV-2, but the sample sizes in those studies were relatively limited (14,45-47). A recent study from Gat et al. [2022] on 37 sperm donors found a temporary decline in sperm concentration and total motile count occurred three months post-vaccination with the BNT162b2 vaccine, and this decline was followed by subsequent recovery (48). While there seems to be limited to no negative impact on sperm quality from COVID-19 vaccination, the damage on sperm quality caused by COVID infection is evident. Previous studies found that SARS-CoV-2 mRNA could be detected in the semen, testis, and prostatic fluid of infected males (7,10). Additionally, patients with moderate COVID symptoms had worse sperm quality parameters after infection compared to the baseline or to patients with mild symptoms and healthy controls (7,49). The impaired sperm quality could be the result of fever or inflammation due to infection.

Moreover, mounting evidence suggests that the COVID-19 vaccination seemingly does not have significant effect on female reproductive health neither. For example, a recent study found that mRNA SARS-CoV-2 vaccination did not significantly change plasma anti-Müllerianhormone (AMH) levels and was not associated with a decrease in ovarian reserve after three months (50). Another assessment on ovarian follicle function reported no measurable difference between vaccinated and unvaccinated women (51). Similarly, recent studies showed the SARS-CoV-2 vaccination had no detrimental effect on sperm numbers and motility among men (14,52-54), whose results are consistent with our outcome.

Individuals contemplating pregnancy face uncertainty surrounding reproductive decision making and provision of care. The absence of data regarding the effect of the pandemic and vaccination on reproductive health accentuated the hurdles faced by those considering pregnancy. Further studies are needed to determine the effects of COVID-19 vaccination on male reproductive health and conception, because results from such studies could help to optimize the decision-making process and management for individuals of reproductive age.

Strengths and limitations

This study utilized a relatively large study population and sample size compared with previous studies. This larger sample size enhances the robustness of our study results. Moreover, our statistical analysis involved the control for potential confounders for sperm quality, including air pollution, lifestyle, habits, and social-demographic characteristics (such as age, education, and BMI). However, since our study population included sperm donor candidates and participation in the study was voluntary, the results must be interpreted cautiously and may have limited generalizability to the broader public. Moreover, not of all subjects who donated sperm before and after vaccination, which is another limitation. And because of the limitation of the cost and conditions, more sperm parameters of the all samples, such as the sperm DNA damage, are not analysed in the study.

Conclusions

In this study, we examined the association between Chinese COVID-19 vaccines and sperm quality parameters. Results from our assessment of repeated semen samples provided by sperm donor candidates suggest that receiving the COVID-19 vaccine is not significantly associated with sperm quality parameters. Individual variability plays the dominant role in explaining the sperm quality variance. Our findings agree with other recent studies and provide additional scientific evidence to guide vaccination policies for reproductive age males.

Acknowledgments

Funding: This work was supported by Sichuan Science and Technology Program (No. 2022YFS0045 and 2023NSFSC1609).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-23-395/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-23-395/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-23-395/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-395/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Institutional Review Board of West China Second University Hospital of Sichuan University (No. WCSUH-SCU IRB 2021-197), and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Huang C, Li B, Xu K, et al. Decline in semen quality among 30,636 young Chinese men from 2001 to 2015. Fertil Steril 2017;107:83-88.e2. [Crossref] [PubMed]
2. Levine H, Jørgensen N, Martino-Andrade A, et al. Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update 2017;23:646-59. [Crossref] [PubMed]
3. Virtanen HE, Jørgensen N, Toppari J. Semen quality in the 21(st) century. Nat Rev Urol 2017;14:120-30. [Crossref] [PubMed]
4. Skakkebaek NE, Rajpert-De Meyts E, Buck Louis GM, et al. Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility. Physiol Rev 2016;96:55-97. [Crossref] [PubMed]
5. Carabelli AM, Peacock TP, Thorne LG, et al. SARS-CoV-2 variant biology: immune escape, transmission and fitness. Nat Rev Microbiol 2023;21:162-77. [Crossref] [PubMed]
6. Mattiuzzi C, Lippi G. COVID-19 vaccination is highly effective to prevent SARS-CoV-2 circulation. J Infect Public Health 2022;15:395-6. [Crossref] [PubMed]
7. He Y, Wang J, Ren J, et al. Effect of COVID-19 on Male Reproductive System - A Systematic Review. Front Endocrinol (Lausanne) 2021;12:677701. [Crossref] [PubMed]
8. Patel DP, Punjani N, Guo J, et al. The impact of SARS-CoV-2 and COVID-19 on male reproduction and men's health. Fertil Steril 2021;115:813-23. [Crossref] [PubMed]
9. Depuydt C, Bosmans E, Jonckheere J, et al. SARS-CoV-2 infection reduces quality of sperm parameters: prospective one year follow-up study in 93 patients. EBioMedicine 2023;93:104640. [Crossref] [PubMed]
10. Holtmann N, Edimiris P, Andree M, et al. Assessment of SARS-CoV-2 in human semen-a cohort study. Fertil Steril 2020;114:233-8. [Crossref] [PubMed]
11. Guo L, Zhao S, Li W, et al. Absence of SARS-CoV-2 in semen of a COVID-19 patient cohort. Andrology 2021;9:42-7. [Crossref] [PubMed]
12. Donders GGG, Bosmans E, Reumers J, et al. Sperm quality and absence of SARS-CoV-2 RNA in semen after COVID-19 infection: a prospective, observational study and validation of the SpermCOVID test. Fertil Steril 2022;117:287-96. [Crossref] [PubMed]
13. Duarte-Neto AN, Teixeira TA, Caldini EG, et al. Testicular pathology in fatal COVID-19: A descriptive autopsy study. Andrology 2022;10:13-23. [Crossref] [PubMed]
14. Reschini M, Pagliardini L, Boeri L, et al. COVID-19 Vaccination Does Not Affect Reproductive Health Parameters in Men. Front Public Health 2022;10:839967. [Crossref] [PubMed]
15. Wang Z, Xu X. scRNA-seq Profiling of Human Testes Reveals the Presence of the ACE2 Receptor, A Target for SARS-CoV-2 Infection in Spermatogonia, Leydig and Sertoli Cells. Cells 2020;9:920. [Crossref] [PubMed]
16. Achua JK, Chu KY, Ibrahim E, et al. Histopathology and Ultrastructural Findings of Fatal COVID-19 Infections on Testis. World J Mens Health 2021;39:65-74. [Crossref] [PubMed]
17. Peirouvi T, Aliaghaei A, Eslami Farsani B, et al. COVID-19 disrupts the blood-testis barrier through the induction of inflammatory cytokines and disruption of junctional proteins. Inflamm Res 2021;70:1165-75. [Crossref] [PubMed]
18. Su S, Du L, Jiang S. Learning from the past: development of safe and effective COVID-19 vaccines. Nat Rev Microbiol 2021;19:211-9. [Crossref] [PubMed]
19. Cai C, Peng Y, Shen E, et al. A comprehensive analysis of the efficacy and safety of COVID-19 vaccines. Mol Ther 2021;29:2794-805. [Crossref] [PubMed]
20. Sharif N, Alzahrani KJ, Ahmed SN, et al. Efficacy, Immunogenicity and Safety of COVID-19 Vaccines: A Systematic Review and Meta-Analysis. Front Immunol 2021;12:714170. [Crossref] [PubMed]
21. Lin Y, Hu Z, Zhao Q, et al. Understanding COVID-19 vaccine demand and hesitancy: A nationwide online survey in China. PLoS Negl Trop Dis 2020;14:e0008961. [Crossref] [PubMed]
22. Fisher KA, Bloomstone SJ, Walder J, et al. Attitudes Toward a Potential SARS-CoV-2 Vaccine: A Survey of U.S. Adults. Ann Intern Med 2020;173:964-73. [Crossref] [PubMed]
23. Dror AA, Eisenbach N, Taiber S, et al. Vaccine hesitancy: the next challenge in the fight against COVID-19. Eur J Epidemiol 2020;35:775-9. [Crossref] [PubMed]
24. Bass SB, Wilson-Genderson M, Garcia DT, et al. SARS-CoV-2 Vaccine Hesitancy in a Sample of US Adults: Role of Perceived Satisfaction With Health, Access to Healthcare, and Attention to COVID-19 News. Front Public Health 2021;9:665724. [Crossref] [PubMed]
25. Lazarus JV, Ratzan SC, Palayew A, et al. A global survey of potential acceptance of a COVID-19 vaccine. Nat Med 2021;27:225-8. [Crossref] [PubMed]
26. Zhang Y, Zeng G, Pan H, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis 2021;21:181-92. [Crossref] [PubMed]
27. Wu Z, Hu Y, Xu M, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis 2021;21:803-12. [Crossref] [PubMed]
28. Yang S, Li Y, Dai L, et al. Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials. Lancet Infect Dis 2021;21:1107-19. [Crossref] [PubMed]
29. Xia S, Duan K, Zhang Y, et al. Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials. JAMA 2020;324:951-60. [Crossref] [PubMed]
30. Zhu FC, Li YH, Guan XH, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet 2020;395:1845-54. [Crossref] [PubMed]
31. Xia S, Zhang Y, Wang Y, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial. Lancet Infect Dis 2021;21:39-51. [Crossref] [PubMed]
32. Wang H, Zhang Y, Huang B, et al. Development of an Inactivated Vaccine Candidate, BBIBP-CorV, with Potent Protection against SARS-CoV-2. Cell 2020;182:713-721.e9. [Crossref] [PubMed]
33. Hirschbühl K, Schaller T, Märkl B, et al. High viral loads: what drives fatal cases of COVID-19 in vaccinees? - an autopsy study. Mod Pathol 2022;35:1013-21. [Crossref] [PubMed]
34. Bando T, Takei R, Mutoh Y, et al. Two cases of acute respiratory failure following SARS-CoV-2 vaccination in post-COVID-19 pneumonia. Respirol Case Rep 2022;10:e0995. [Crossref] [PubMed]
35. Cheng H, Peng Z, Luo W, et al. Efficacy and Safety of COVID-19 Vaccines in Phase III Trials: A Meta-Analysis. Vaccines (Basel) 2021;9:582. [Crossref] [PubMed]
36. Pormohammad A, Zarei M, Ghorbani S, et al. Efficacy and Safety of COVID-19 Vaccines: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Vaccines (Basel) 2021;9:467. [Crossref] [PubMed]
37. Fiolet T, Kherabi Y, MacDonald CJ, et al. Comparing COVID-19 vaccines for their characteristics, efficacy and effectiveness against SARS-CoV-2 and variants of concern: a narrative review. Clin Microbiol Infect 2022;28:202-21. [Crossref] [PubMed]
38. Qiu Y, Yang T, Seyler BC, et al. Ambient air pollution and male fecundity: A retrospective analysis of longitudinal data from a Chinese human sperm bank (2013-2018). Environ Res 2020;186:109528. [Crossref] [PubMed]
39. Yang T, Deng L, Sun B, et al. Semen quality and windows of susceptibility: A case study during COVID-19 outbreak in China. Environ Res 2021;197:111085. [Crossref] [PubMed]
40. Di Q, Kloog I, Koutrakis P, et al. Assessing PM2.5 Exposures with High Spatiotemporal Resolution across the Continental United States. Environ Sci Technol 2016;50:4712-21. [Crossref] [PubMed]
41. Wang W, Liu X, Bi J, et al. A machine learning model to estimate ground-level ozone concentrations in California using TROPOMI data and high-resolution meteorology. Environ Int 2022;158:106917. [Crossref] [PubMed]
42. Wu S, Huang B, Wang J, et al. Spatiotemporal mapping and assessment of daily ground NO2 concentrations in China using high-resolution TROPOMI retrievals. Environ Pollut 2021; Epub ahead of print. [Crossref] [PubMed]
43. Zhan Y, Luo Y, Deng X, et al. Satellite-Based Estimates of Daily NO(2) Exposure in China Using Hybrid Random Forest and Spatiotemporal Kriging Model. Environ Sci Technol 2018;52:4180-9. [Crossref] [PubMed]
44. Zhan Y, Luo Y, Deng X, et al. Spatiotemporal prediction of daily ambient ozone levels across China using random forest for human exposure assessment. Environ Pollut 2018;233:464-73. [Crossref] [PubMed]
45. Gonzalez DC, Nassau DE, Khodamoradi K, et al. Sperm Parameters Before and After COVID-19 mRNA Vaccination. JAMA 2021;326:273-4. [Crossref] [PubMed]
46. Safrai M, Herzberg S, Imbar T, et al. The BNT162b2 mRNA Covid-19 vaccine does not impair sperm parameters. Reprod Biomed Online 2022;44:685-8. [Crossref] [PubMed]
47. Lifshitz D, Haas J, Lebovitz O, et al. Does mRNA SARS-CoV-2 vaccine detrimentally affect male fertility, as reflected by semen analysis? Reprod Biomed Online 2022;44:145-9. [Crossref] [PubMed]
48. Gat I, Kedem A, Dviri M, et al. Covid-19 vaccination BNT162b2 temporarily impairs semen concentration and total motile count among semen donors. Andrology 2022;10:1016-22. [Crossref] [PubMed]
49. Erbay G, Sanli A, Turel H, et al. Short-term effects of COVID-19 on semen parameters: A multicenter study of 69 cases. Andrology 2021;9:1060-5. [Crossref] [PubMed]
50. Mohr-Sasson A, Haas J, Abuhasira S, et al. The effect of Covid-19 mRNA vaccine on serum anti-Müllerian hormone levels. Hum Reprod 2022;37:534-41. [Crossref] [PubMed]
51. Bentov Y, Beharier O, Moav-Zafrir A, et al. Ovarian follicular function is not altered by SARS-CoV-2 infection or BNT162b2 mRNA COVID-19 vaccination. Hum Reprod 2021;36:2506-13. [Crossref] [PubMed]
52. Huang J, Xia L, Tian L, et al. Comparison of Semen Quality Before and After Inactivated SARS-CoV-2 Vaccination Among Men in China. JAMA Netw Open 2022;5:e2230631. [Crossref] [PubMed]
53. Zhu H, Wang X, Zhang F, et al. Evaluation of inactivated COVID-19 vaccine on semen parameters in reproductive-age males: a retrospective cohort study. Asian J Androl 2022;24:441-4. [Crossref] [PubMed]
54. Massarotti C, Stigliani S, Maccarini E, et al. mRNA and Viral Vector COVID-19 Vaccines Do Not Affect Male Fertility: A Prospective Study. World J Mens Health 2022;40:561-9. [Crossref] [PubMed]