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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Immunol.</journal-id>
<journal-title>Frontiers in Immunology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Immunol.</abbrev-journal-title>
<issn pub-type="epub">1664-3224</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fimmu.2024.1321406</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Immunology</subject>
<subj-group>
<subject>Original Research</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Comprehensive evaluation of inactivated SARS-CoV-2 vaccination on sperm parameters and sex hormones</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Dong</surname>
<given-names>Yehao</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2644247"/>
<role content-type="https://credit.niso.org/contributor-roles/conceptualization/"/>
<role content-type="https://credit.niso.org/contributor-roles/formal-analysis/"/>
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<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ba</surname>
<given-names>Zaihua</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2659204"/>
<role content-type="https://credit.niso.org/contributor-roles/conceptualization/"/>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Qin</surname>
<given-names>Yining</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2659195"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ma</surname>
<given-names>Jiao</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2659196"/>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Li</surname>
<given-names>Yuqi</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2659188"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Zhang</surname>
<given-names>Yingze</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2659190"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Yang</surname>
<given-names>Aijun</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/conceptualization/"/>
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</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Chen</surname>
<given-names>Fei</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1283641"/>
<role content-type="https://credit.niso.org/contributor-roles/conceptualization/"/>
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<xref ref-type="author-notes" rid="fn003">
<sup>&#x2020;</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1">
<sup>1</sup>
<institution>Center for Reproductive Medicine, Affiliated Hospital of Jining Medical University</institution>, <addr-line>Jining</addr-line>, <country>China</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Department of Physiology, Jining Medical University</institution>, <addr-line>Jining</addr-line>, <country>China</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>Edited by: Sunny Abarikwu, University of Port Harcourt, Nigeria</p>
</fn>
<fn fn-type="edited-by">
<p>Reviewed by: Thiago Afonso Teixeira, University of S&#xe3;o Paulo, Brazil</p>
<p>Vidyleison Neves Camargos, University of Texas Medical Branch at Galveston, United States</p>
</fn>
<fn fn-type="corresp" id="fn001">
<p>*Correspondence: Fei Chen, <email xlink:href="mailto:chenfei0336@163.com">chenfei0336@163.com</email>
</p>
</fn>
<fn fn-type="other" id="fn003">
<p>&#x2020;ORCID: Fei Chen, <uri xlink:href="https://orcid.org/0000-0002-2578-7159">orcid.org/0000-0002-2578-7159</uri>
</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>26</day>
<month>02</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>15</volume>
<elocation-id>1321406</elocation-id>
<history>
<date date-type="received">
<day>14</day>
<month>10</month>
<year>2023</year>
</date>
<date date-type="accepted">
<day>09</day>
<month>02</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2024 Dong, Ba, Qin, Ma, Li, Zhang, Yang and Chen</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Dong, Ba, Qin, Ma, Li, Zhang, Yang and Chen</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<sec>
<title>Background</title>
<p>The inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine has made significant contributions to fighting the epidemic in the past three years. However, the rapid development and application raised concerns about its safety in reproductive health, especially after several studies had observed a decrease in semen parameters following two doses of mRNA SARS-CoV-2 vaccination. Thus, it is necessary to comprehensively evaluate the effect of inactivated SARS-CoV-2 vaccine on male fertility.</p>
</sec>
<sec>
<title>Methods</title>
<p>A retrospective cohort study was conducted in the Center for Reproductive Medicine of the Affiliated Hospital of Jining Medical University between July 2021 and March 2023.&#xa0;A total of 409 men with different vaccination status and no history of SARS-CoV-2 infection were included in this study. Their sex hormone levels and semen parameters were evaluated and compared separately.</p>
</sec>
<sec>
<title>Results</title>
<p>The levels of FSH and PRL in one-dose vaccinated group were higher than other groups, while there were no significant changes in other sex hormone levels between the control and inactivated SARS-CoV-2 vaccinated groups. Most semen parameters such as volume, sperm concentration, total sperm count, progressive motility and normal forms were similar before and after vaccination with any single dose or combination of doses (all <italic>P</italic> &gt; 0.05). Nevertheless, the total motility was significantly decreased after receiving the 1&#xa0;+&#xa0;2 doses of vaccine compared to before vaccination (46.90 &#xb1; 2.40% <italic>vs</italic>. 58.62 &#xb1; 2.51%; <italic>P</italic> = 0.001). Fortunately, this parameter was still within the normal range.</p>
</sec>
<sec>
<title>Conclusion</title>
<p>Our study demonstrated that any single dose or different combined doses of inactivated SARS-CoV-2 vaccination was not detrimental to male fertility. This information could reassure men who want to conceive after vaccination and be incorporated into future fertility recommendations.</p>
</sec>
</abstract>
<kwd-group>
<kwd>inactivated SARS-CoV-2 vaccine</kwd>
<kwd>semen parameters</kwd>
<kwd>sex hormones</kwd>
<kwd>China</kwd>
<kwd>SARS-CoV-2</kwd>
<kwd>COVID-19</kwd>
<kwd>male fertility</kwd>
</kwd-group>
<contract-sponsor id="cn001">Natural Science Foundation of Shandong Province<named-content content-type="fundref-id">10.13039/501100007129</named-content>
</contract-sponsor>
<counts>
<fig-count count="0"/>
<table-count count="2"/>
<equation-count count="0"/>
<ref-count count="62"/>
<page-count count="8"/>
<word-count count="4329"/>
</counts>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-in-acceptance</meta-name>
<meta-value>Vaccines and Molecular Therapeutics</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1" sec-type="intro">
<label>1</label>
<title>Introduction</title>
<p>The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has triggered a worldwide health emergency of an unparalleled scale. As of January 2024, over 774 million infected cases and 7.0 million fatalities have been recorded globally (<xref ref-type="bibr" rid="B1">1</xref>). In most healthy adults and children, the disease is usually mild or asymptomatic. Common clinical symptoms include fever, cough, myalgia or fatigue, expectoration, and dyspnea (<xref ref-type="bibr" rid="B2">2</xref>). However, the illness may be severe and even fatal in some patients, especially the elderly and those with underlying diseases (<xref ref-type="bibr" rid="B3">3</xref>). As well known, before a highly specific drug is developed, large-scale vaccination is the important approach to mitigate disease and build herd immunity against this pandemic. By 26 November 2023, a total of 13.59 billion vaccine doses have been administered (<xref ref-type="bibr" rid="B1">1</xref>), and they successfully reduced the rates of infections, severity, hospitalization and mortality among the different populations (<xref ref-type="bibr" rid="B4">4</xref>). Even for XBB.1.5, the most recent Omicron subvariant, vaccination still confers some levels of protection against it, especially against severe disease (<xref ref-type="bibr" rid="B5">5</xref>&#x2013;<xref ref-type="bibr" rid="B7">7</xref>). Currently, there are more than 183 vaccine candidates in clinical trials, and 14 of them have been granted emergency use authorization (<xref ref-type="bibr" rid="B8">8</xref>). Among them, Sinovac/CoronaVac and Sinopharm BBIBP-CorV are predominantly used in China and approved in other 114 countries such as Brazil, Chile, Indonesia, Mexico, and Turkey (<xref ref-type="bibr" rid="B9">9</xref>). Both of them are inactivated vaccines, which administer the virus in a chemically inactivated form that is unable to replicate. The main antigenic components that induce immune responses are retained, and additionally, aluminum hydroxide is added as an adjuvant to strengthen the immune response. Although the neutralizing antibody titres in individuals who vaccinated with inactivated vaccine were lower than with mRNA vaccine (<xref ref-type="bibr" rid="B10">10</xref>), the efficacy of CoronaVac in preventing the need for assistance (defined as a score &#x2265;3 on the WHO Clinical Progression Scale) could still be as high as 83.7% (<xref ref-type="bibr" rid="B11">11</xref>). Similarly, in a randomized clinical trial involving 40,382 participants, vaccination of adults with Sinopharm BBIBP and WIBP vaccines markedly decreased the risk of symptomatic COVID-19, and serious adverse events were rare (<xref ref-type="bibr" rid="B12">12</xref>). Moreover, because of their long shelf life without the need for ultracold chain storage, inactivated vaccine has been proposed to be a near-ideal candidate for mass immunization programs in less wealthy nations (<xref ref-type="bibr" rid="B12">12</xref>, <xref ref-type="bibr" rid="B13">13</xref>).</p>
<p>With the implementation of the inactivated COVID-19 vaccination, questions regarding the impact of the vaccine on male reproductive health have arisen. In this regard, Zhu et&#xa0;al. observed that there were no significant differences in semen parameters (volume, sperm concentration, progressive motility and total progressive motile count) before and after receiving first or second dose of the vaccine (<xref ref-type="bibr" rid="B14">14</xref>). Our previous study also showed similar results (<xref ref-type="bibr" rid="B15">15</xref>). However, these studies focused on evaluating the effect of each individual dose vaccination, while the influence of combined doses of vaccines on human fertility has not been assessed in detail. Although some studies have found a temporary decrease in sperm concentration and total sperm motility after 1&#xa0;+&#xa0;2 doses of mRNA vaccination compared to unvaccinated men, whether this conclusion applies to inactivated vaccines remains to be verified (<xref ref-type="bibr" rid="B16">16</xref>, <xref ref-type="bibr" rid="B17">17</xref>). Moreover, most of the participants included in previous studies on inactivated vaccines underwent semen analysis only once, making it difficult to use a pre and post control group design to eliminate confounding factors and selection bias (<xref ref-type="bibr" rid="B15">15</xref>, <xref ref-type="bibr" rid="B18">18</xref>, <xref ref-type="bibr" rid="B19">19</xref>). Therefore, we performed this study to comprehensively investigate the effect of inactivated COVID-19 vaccination on male fertility, hoping to provide more valuable information for future public health efforts.</p>
</sec>
<sec id="s2" sec-type="materials|methods">
<label>2</label>
<title>Materials and methods</title>
<sec id="s2_1">
<label>2.1</label>
<title>Study design and setting</title>
<p>This is a retrospective cohort study conducted in the Center for Reproductive Medicine of the Affiliated Hospital of Jining Medical University between July 2021 and March 2023. The study protocol obtained approval from the Ethics Committee.</p>
</sec>
<sec id="s2_2">
<label>2.2</label>
<title>Participant selection</title>
<p>The study included 409 men aged between 22 and 49 years who had attended the center for reproductive problems or routine examination. Men who were tested positive for SARS-CoV-2 at any point or were taking medications such as supplemental testosterone or anabolic steroids were excluded.</p>
<p>Two sets of comparative observations were conducted simultaneously. One was the comparison of sex hormone levels before and after inactivated SARS-CoV-2 vaccination. Another was to evaluate the effect of each dose or combination of doses of vaccination on semen parameters. Based on their vaccination status, subjects participating in the first comparison were categorized into four groups: unvaccinated group (group A, n = 110), one-dose vaccinated group (group B, n = 11), fully vaccinated group (group C, n = 156), and booster group (group D, n = 106). In the second evaluation, participants had at least two semen analyses and were categorized into six groups according to the time point of each analysis: before and after the first dose of vaccine (group A1, n = 3), before and after the second dose of vaccine (group B1, n = 10), before and after the booster dose of vaccine (group C1, n = 40), before and after 1&#xa0;+&#xa0;2 doses of vaccine (group D1, n = 56), before and after 2&#xa0;+&#xa0;3 doses of vaccine (group E1, n = 7), before and after 1&#xa0;+&#xa0;2&#xa0;+&#xa0;3 doses of vaccine (group F1, n = 28).</p>
<p>Sex hormonal analysis: Fasting blood samples were obtained from participants for sex hormonal analysis. Serum levels of follicle-stimulating hormone (FSH), estradiol (E2), prolactin (PRL), testosterone (T) and luteinizing hormone (LH) were determined via the Unicel Dxi 800 Access Immunoassay System (Beckman Coulter Inc.). At the same time, we also calculated T/LH ratio, which is a valuable indicator of Leydig cell function (<xref ref-type="bibr" rid="B20">20</xref>, <xref ref-type="bibr" rid="B21">21</xref>).</p>
<p>Semen analysis: Following a 2&#x2013;7-day abstinence period, each subject provided a fresh semen sample in a sterile vessel by means of masturbation. The samples were liquefied at room temperature for 30&#x2013;60 min and then evaluated according to Laboratory Manual for the Examination and Processing of Human Sperm (5th Edition) (<xref ref-type="bibr" rid="B22">22</xref>). Semen volume and morphology were determined with the help of graduated tube and Diff Quick Staining Kit (Huakang Biomed Ltd.), respectively. Other parameters included sperm concentration, total sperm count, progressive motility and total motility were analyzed by computer-assisted sperm analysis system (SAS Medical Co., Ltd.).</p>
</sec>
<sec id="s2_3">
<label>2.3</label>
<title>Data collection</title>
<p>The baseline (age, height, and weight) and clinical data were extracted from the patients&#x2019; medical record. Other details including vaccination date and type of vaccine administered were gathered through interviews.</p>
</sec>
<sec id="s2_4">
<label>2.4</label>
<title>Data analysis</title>
<p>In this retrospective cohort study, SPSS 27.0 (SPSS Inc.) was used for all statistical analysis. For continuous variables, the data were represented as mean &#xb1; standard error (SE) and compared by one-way analysis of variance and Duncan&#x2019;s multiple range test. Categorical variables were expressed as numbers (n) and percentages (%) of the total and analyzed using &#x3c7;<sup>2</sup> test or the Fisher exact test (samples with expectancy of less than 5). Differences among groups were considered as statistically significant when <italic>P</italic> &lt; 0.05.</p>
</sec>
</sec>
<sec id="s3" sec-type="results">
<label>3</label>
<title>Results</title>
<p>The sociodemographic characteristics and sex hormone levels of 383 subjects were described in <xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>. There were no statistically significant differences in age (<italic>P</italic> = 0.056) and BMI (<italic>P</italic> = 0.250) between the control and inactivated SARS-CoV-2 vaccinated groups. Most subjects were healthy without a history of testicular surgery. Pernicious habits such as smoking and alcohol abuse were rare.</p>
<table-wrap id="T1" position="float">
<label>Table&#xa0;1</label>
<caption>
<p>Sociodemographic characteristics of the men enrolled in the study and sex hormone levels before and after vaccination.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="middle" rowspan="2" align="center">Parameter</th>
<th valign="top" align="center">Group A <break/>(n = 110)</th>
<th valign="top" align="center">Group B<break/>(n = 11)</th>
<th valign="top" align="center">Group C <break/>(n = 156)</th>
<th valign="top" align="center">Group D <break/>(n = 106)</th>
<th valign="middle" rowspan="2" align="center">
<italic>P</italic> value</th>
<th valign="middle" rowspan="2" align="center">Statistical test</th>
</tr>
<tr>
<th valign="top" align="center">Unvaccinated group</th>
<th valign="top" align="center">One-dose <break/>vaccinated group</th>
<th valign="top" align="center">Fully <break/>vaccinated group</th>
<th valign="top" align="center">Booster group</th>
</tr>
</thead>
<tbody>
<tr>
<th valign="top" colspan="7" align="left">Participants&#x2019; characteristics</th>
</tr>
<tr>
<td valign="top" align="left">Age (years), mean &#xb1; SE</td>
<td valign="top" align="center">31.26 &#xb1; 0.46<sup>a</sup>
</td>
<td valign="top" align="center">33.27 &#xb1; 1.48<sup>a</sup>
</td>
<td valign="top" align="center">33.03 &#xb1; 0.40<sup>a</sup>
</td>
<td valign="top" align="center">33.81 &#xb1; 0.53<sup>a</sup>
</td>
<td valign="top" align="center">0.056</td>
<td valign="top" align="center">one-way ANOVA test</td>
</tr>
<tr>
<td valign="top" align="left">BMI (kg/m<sup>2</sup>), mean &#xb1; SE</td>
<td valign="top" align="center">26.85 &#xb1; 0.40<sup>a</sup>
</td>
<td valign="top" align="center">25.91 &#xb1; 1.36<sup>a</sup>
</td>
<td valign="top" align="center">26.65 &#xb1; 0.34<sup>a</sup>
</td>
<td valign="top" align="center">25.62 &#xb1; 0.34<sup>a</sup>
</td>
<td valign="top" align="center">0.250</td>
<td valign="top" align="center">one-way ANOVA test</td>
</tr>
<tr>
<td valign="top" align="left">Smoking % (n/total)</td>
<td valign="top" align="center">6.36 (7/110)<sup>a</sup>
</td>
<td valign="top" align="center">9.09 (1/11)<sup>a</sup>
</td>
<td valign="top" align="center">7.05 (11/156)<sup>a</sup>
</td>
<td valign="top" align="center">11.32 (12/106)<sup>a</sup>
</td>
<td valign="top" align="center">0.473</td>
<td valign="top" align="center">Fisher exact test</td>
</tr>
<tr>
<td valign="top" align="left">Alcohol consumption % (n/total)</td>
<td valign="top" align="center">0 (0/110)<sup>a</sup>
</td>
<td valign="top" align="center">0 (0/11)<sup>a</sup>
</td>
<td valign="top" align="center">0 (0/156)<sup>a</sup>
</td>
<td valign="top" align="center">0.94 (1/106)<sup>a</sup>
</td>
<td valign="top" align="center">0.305</td>
<td valign="top" align="center">Fisher exact test</td>
</tr>
<tr>
<td valign="top" align="left">Testes surgery % (n/total)</td>
<td valign="top" align="center">0.91 (1/110)<sup>a</sup>
</td>
<td valign="top" align="center">0 (0/11)<sup>a</sup>
</td>
<td valign="top" align="center">0 (0/156)<sup>a</sup>
</td>
<td valign="top" align="center">0.94 (1/106)<sup>a</sup>
</td>
<td valign="top" align="center">0.374</td>
<td valign="top" align="center">Fisher exact test</td>
</tr>
<tr>
<th valign="top" colspan="7" align="left">Sex hormone</th>
</tr>
<tr>
<td valign="top" align="left">T (ng/mL), mean &#xb1; SE</td>
<td valign="top" align="center">3.78 &#xb1; 0.13<sup>a</sup>
</td>
<td valign="top" align="center">3.83 &#xb1; 0.31<sup>a</sup>
</td>
<td valign="top" align="center">3.56 &#xb1; 0.09<sup>a</sup>
</td>
<td valign="top" align="center">3.92 &#xb1; 0.15<sup>a</sup>
</td>
<td valign="top" align="center">0.309</td>
<td valign="top" align="center">one-way ANOVA test</td>
</tr>
<tr>
<td valign="top" align="left">LH (mIU/mL), mean &#xb1; SE</td>
<td valign="top" align="center">3.92 &#xb1; 0.21<sup>a</sup>
</td>
<td valign="top" align="center">4.88 &#xb1; 1.22<sup>a</sup>
</td>
<td valign="top" align="center">3.79 &#xb1; 0.15<sup>a</sup>
</td>
<td valign="top" align="center">4.04 &#xb1; 0.21<sup>a</sup>
</td>
<td valign="top" align="center">0.050</td>
<td valign="top" align="center">one-way ANOVA test</td>
</tr>
<tr>
<td valign="top" align="left">T/LH ratio, mean &#xb1; SE</td>
<td valign="top" align="center">1.20 &#xb1; 0.06<sup>a</sup>
</td>
<td valign="top" align="center">1.12 &#xb1; 0.18<sup>a</sup>
</td>
<td valign="top" align="center">1.10 &#xb1; 0.04<sup>a</sup>
</td>
<td valign="top" align="center">1.20 &#xb1; 0.07<sup>a</sup>
</td>
<td valign="top" align="center">0.571</td>
<td valign="top" align="center">one-way ANOVA test</td>
</tr>
<tr>
<td valign="top" align="left">FSH (mIU/mL), mean &#xb1; SE</td>
<td valign="top" align="center">6.21 &#xb1; 0.57<sup>a</sup>
</td>
<td valign="top" align="center">8.78 &#xb1; 1.72<sup>b</sup>
</td>
<td valign="top" align="center">5.85 &#xb1; 0.23<sup>a</sup>
</td>
<td valign="top" align="center">5.75 &#xb1; 0.36<sup>a</sup>
</td>
<td valign="top" align="center">&#x2013;</td>
<td valign="top" align="center">one-way ANOVA test</td>
</tr>
<tr>
<td valign="top" align="left">E2 (pg/mL), mean &#xb1; SE</td>
<td valign="top" align="center">32.53 &#xb1; 1.52<sup>a</sup>
</td>
<td valign="top" align="center">32.20 &#xb1; 4.14<sup>a</sup>
</td>
<td valign="top" align="center">35.51 &#xb1; 1.08<sup>a</sup>
</td>
<td valign="top" align="center">33.24 &#xb1; 1.30<sup>a</sup>
</td>
<td valign="top" align="center">0.386</td>
<td valign="top" align="center">one-way ANOVA test</td>
</tr>
<tr>
<td valign="top" align="left">PRL (ng/mL), mean &#xb1; SE</td>
<td valign="top" align="center">10.40 &#xb1; 0.43<sup>a</sup>
</td>
<td valign="top" align="center">13.49 &#xb1; 1.34<sup>b</sup>
</td>
<td valign="top" align="center">10.06 &#xb1; 0.31<sup>a</sup>
</td>
<td valign="top" align="center">11.56 &#xb1; 0.57<sup>ab</sup>
</td>
<td valign="top" align="center">&#x2013;</td>
<td valign="top" align="center">one-way ANOVA test</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>BMI, body mass index; T, testosterone; LH, luteinizing hormone; FSH, follicle&#x2010;stimulating hormone; E2, estradiol; PRL, prolactin; &#x2013;, not applicable.</p>
</fn>
<fn>
<p>
<sup>a,b</sup>Values without a common letter in their superscripts differ significantly (P &lt; 0.05).</p>
</fn>
</table-wrap-foot>
</table-wrap>
<p>Sex hormonal analysis revealed that the levels of most hormones were similar among the unvaccinated, first-dose, second-dose, and booster vaccinated groups. Specifically, no significant differences were observed in T levels between the four groups (3.78 &#xb1; 0.13 vs. 3.83 &#xb1; 0.31 vs. 3.56 &#xb1; 0.09 vs. 3.92 &#xb1; 0.15 ng/mL). The serum LH levels showed no significant changes in patients who received any dose of inactivated SARS-CoV-2 vaccine compared to controls (3.92 &#xb1; 0.21 vs. 4.88 &#xb1; 1.22 vs. 3.79 &#xb1; 0.15 vs. 4.04 &#xb1; 0.21 mIU/mL). Moreover, we did not observe significant differences when T/LH ratios were compared (1.20 &#xb1; 0.06 vs. 1.12 &#xb1; 0.18 vs. 1.10 &#xb1; 0.04 vs. 1.20 &#xb1; 0.07). The serum E2 concentrations were also comparable between all groups (32.53 &#xb1; 1.52 vs. 32.20 &#xb1; 4.14 vs. 35.51 &#xb1; 1.08 vs. 33.24 &#xb1; 1.30 pg/mL). However, the FSH and PRL showed a highly significant increase in the first-dose vaccinated group, possibly due to the small sample size (n = 11).</p>
<p>
<xref ref-type="table" rid="T2">
<bold>Table&#xa0;2</bold>
</xref> showed the comparison of sperm parameters of the participants before and after vaccination. According to current data, vaccination with any single dose did not affect semen volume, sperm concentration, total sperm count, progressive motility, total motility, and normal forms. Most parameters of participants who received a combined dose of vaccine also yielded similar results. Nevertheless, compared to before vaccination, the total motility decreased substantially after fully vaccination (58.62 &#xb1; 2.51% vs. 46.90 &#xb1; 2.40%; <italic>P</italic> = 0.001). Fortunately, this parameter was still above the lower reference limit of WHO 5th edition [40% (38&#x2013;42%)] (<xref ref-type="bibr" rid="B22">22</xref>). In addition, the average normal sperm morphologies of participants in both the control and vaccinated groups were below the recommended threshold of 4%. This may be due to the abstract criteria for sperm morphology defects, making it difficult for evaluators to give an accurate assessment. Moreover, the considerable heterogeneity in preparation, fixation, staining and smear reading techniques also has a serious impact on the sperm morphology evaluation results.</p>
<table-wrap id="T2" position="float">
<label>Table&#xa0;2</label>
<caption>
<p>Comparison of semen parameters before and after each dose or combination of doses of inactivated SARS-CoV-2 vaccine.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="middle" rowspan="2" align="center">Parameter</th>
<th valign="top" colspan="2" align="center">Group A1</th>
<th valign="top" rowspan="2" align="center">
<italic>P</italic> value</th>
<th valign="top" colspan="2" align="center">Group B1</th>
<th valign="top" rowspan="2" align="center">
<italic>P</italic> value</th>
<th valign="top" colspan="2" align="center">Group C1</th>
<th valign="top" rowspan="2" align="center">
<italic>P</italic> value</th>
<th valign="top" colspan="2" align="center">Group D1</th>
<th valign="top" rowspan="2" align="center">
<italic>P</italic> value</th>
<th valign="top" colspan="2" align="center">Group E1</th>
<th valign="top" rowspan="2" align="center">
<italic>P</italic> value</th>
<th valign="top" colspan="2" align="center">Group F1</th>
<th valign="top" rowspan="2" align="center">
<italic>P</italic> value</th>
<th valign="middle" rowspan="2" align="center">WHO reference 5th percentile (median)</th>
</tr>
<tr>
<th valign="top" align="center">Before 1st dose of vaccine</th>
<th valign="top" align="center">After 1st dose of vaccine</th>
<th valign="top" align="center">Before 2nd dose of vaccine</th>
<th valign="top" align="center">After 2nd dose of vaccine</th>
<th valign="top" align="center">Before booster dose of vaccine</th>
<th valign="top" align="center">After booster dose of vaccine</th>
<th valign="top" align="center">Before 1&#xa0;+&#xa0;2 doses of vaccine</th>
<th valign="top" align="center">After 1&#xa0;+&#xa0;2 doses of vaccine</th>
<th valign="top" align="center">Before 2&#xa0;+&#xa0;3 doses of vaccine</th>
<th valign="top" align="center">After 2&#xa0;+&#xa0;3 doses of vaccine</th>
<th valign="top" align="center">Before 1&#xa0;+&#xa0;2&#xa0;+&#xa0;3 doses of vaccine</th>
<th valign="top" align="center">After 1&#xa0;+&#xa0;2&#xa0;+&#xa0;3 doses of vaccine</th>
</tr>
</thead>
<tbody>
<tr>
<th valign="top" colspan="20" align="left">Participants&#x2019; Characteristic</th>
</tr>
<tr>
<td valign="top" align="left">Age (years), mean &#xb1; SE</td>
<td valign="top" colspan="2" align="center">28.67 &#xb1; 1.33</td>
<td valign="top" align="center"/>
<td valign="top" colspan="2" align="center">32.10 &#xb1; 1.74</td>
<td valign="top" align="center"/>
<td valign="top" colspan="2" align="center">32.13 &#xb1; 0.70</td>
<td valign="top" align="center"/>
<td valign="top" colspan="2" align="center">31.38 &#xb1; 0.62</td>
<td valign="top" align="center"/>
<td valign="top" colspan="2" align="center">30.71 &#xb1; 1.27</td>
<td valign="top" align="center"/>
<td valign="top" colspan="2" align="center">31.93 &#xb1; 0.82</td>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
</tr>
<tr>
<td valign="top" align="left">BMI (kg/m<sup>2</sup>), mean &#xb1; SE</td>
<td valign="top" colspan="2" align="center">27.20 &#xb1; 3.74</td>
<td valign="top" align="center"/>
<td valign="top" colspan="2" align="center">24.82 &#xb1; 1.60</td>
<td valign="top" align="center"/>
<td valign="top" colspan="2" align="center">27.38 &#xb1; 0.71</td>
<td valign="top" align="center"/>
<td valign="top" colspan="2" align="center">26.96 &#xb1; 0.50</td>
<td valign="top" align="center"/>
<td valign="top" colspan="2" align="center">25.23 &#xb1; 1.06</td>
<td valign="top" align="center"/>
<td valign="top" colspan="2" align="center">25.92 &#xb1; 0.69</td>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
</tr>
<tr>
<th valign="top" colspan="20" align="left">Semen parameter</th>
</tr>
<tr>
<td valign="top" align="left">Time from vaccination to semen sample collection (days), mean &#xb1; SE</td>
<td valign="top" align="center">&#x2013;</td>
<td valign="top" align="center">12.00 &#xb1; 8.00</td>
<td valign="top" align="center">&#x2013;</td>
<td valign="top" align="center">&#x2013;</td>
<td valign="top" align="center">43.80 &#xb1; 17.90</td>
<td valign="top" align="center">&#x2013;</td>
<td valign="top" align="center">&#x2013;</td>
<td valign="top" align="center">61.58 &#xb1; 9.19</td>
<td valign="top" align="center">&#x2013;</td>
<td valign="top" align="center">&#x2013;</td>
<td valign="top" align="center">107.30 &#xb1; 7.72</td>
<td valign="top" align="center">&#x2013;</td>
<td valign="top" align="center">&#x2013;</td>
<td valign="top" align="center">52.29 &#xb1; 19.01</td>
<td valign="top" align="center">&#x2013;</td>
<td valign="top" align="center">&#x2013;</td>
<td valign="top" align="center">75.64 &#xb1; 10.28</td>
<td valign="top" align="center">&#x2013;</td>
<td valign="top" align="center">&#x2013;</td>
</tr>
<tr>
<td valign="top" align="left">Sexual abstinence (days), mean &#xb1; SE</td>
<td valign="top" align="center">3.67 &#xb1; 1.67</td>
<td valign="top" align="center">4.67 &#xb1; 1.20</td>
<td valign="top" align="center">0.654</td>
<td valign="top" align="center">4.40 &#xb1; 0.56</td>
<td valign="top" align="center">3.70 &#xb1; 0.34</td>
<td valign="top" align="center">0.302</td>
<td valign="top" align="center">4.00 &#xb1; 0.31</td>
<td valign="top" align="center">4.00 &#xb1; 0.32</td>
<td valign="top" align="center">1.000</td>
<td valign="top" align="center">4.25 &#xb1; 0.25</td>
<td valign="top" align="center">4.21 &#xb1; 0.25</td>
<td valign="top" align="center">0.919</td>
<td valign="top" align="center">4.29 &#xb1; 0.75</td>
<td valign="top" align="center">3.00 &#xb1; 0.38</td>
<td valign="top" align="center">0.159</td>
<td valign="top" align="center">3.79 &#xb1; 0.33</td>
<td valign="top" align="center">3.57 &#xb1; 0.31</td>
<td valign="top" align="center">0.641</td>
<td valign="top" align="center">2-7</td>
</tr>
<tr>
<td valign="top" align="left">Semen volume (ml), mean &#xb1; SE</td>
<td valign="top" align="center">3.67 &#xb1; 0.44</td>
<td valign="top" align="center">4.37 &#xb1; 0.45</td>
<td valign="top" align="center">0.328</td>
<td valign="top" align="center">3.56 &#xb1; 0.52</td>
<td valign="top" align="center">3.28 &#xb1; 0.60</td>
<td valign="top" align="center">0.728</td>
<td valign="top" align="center">3.69 &#xb1; 0.28</td>
<td valign="top" align="center">3.77 &#xb1; 0.29</td>
<td valign="top" align="center">0.834</td>
<td valign="top" align="center">3.89 &#xb1; 0.20</td>
<td valign="top" align="center">3.79 &#xb1; 0.23</td>
<td valign="top" align="center">0.743</td>
<td valign="top" align="center">4.04 &#xb1; 0.55</td>
<td valign="top" align="center">3.83 &#xb1; 0.73</td>
<td valign="top" align="center">0.818</td>
<td valign="top" align="center">3.60 &#xb1; 0.30</td>
<td valign="top" align="center">3.54 &#xb1; 0.30</td>
<td valign="top" align="center">0.892</td>
<td valign="top" align="center">1.5</td>
</tr>
<tr>
<td valign="top" align="left">Sperm concentration (10<sup>6</sup> per ml), mean &#xb1; SE</td>
<td valign="top" align="center">25.43 &#xb1; 1.14</td>
<td valign="top" align="center">20.10 &#xb1; 3.91</td>
<td valign="top" align="center">0.305</td>
<td valign="top" align="center">46.45 &#xb1; 13.96</td>
<td valign="top" align="center">41.30 &#xb1; 13.77</td>
<td valign="top" align="center">0.796</td>
<td valign="top" align="center">25.62 &#xb1; 3.22</td>
<td valign="top" align="center">33.10 &#xb1; 4.50</td>
<td valign="top" align="center">0.181</td>
<td valign="top" align="center">33.06 &#xb1; 2.89</td>
<td valign="top" align="center">34.71 &#xb1; 3.62</td>
<td valign="top" align="center">0.723</td>
<td valign="top" align="center">23.80 &#xb1; 5.52</td>
<td valign="top" align="center">26.93 &#xb1; 9.02</td>
<td valign="top" align="center">0.773</td>
<td valign="top" align="center">27.67 &#xb1; 4.12</td>
<td valign="top" align="center">33.79 &#xb1; 4.94</td>
<td valign="top" align="center">0.345</td>
<td valign="top" align="center">15</td>
</tr>
<tr>
<td valign="top" align="left">Total sperm count (10<sup>6</sup> per ejaculate), mean &#xb1; SE</td>
<td valign="top" align="center">94.04 &#xb1; 15.24</td>
<td valign="top" align="center">86.60 &#xb1; 17.64</td>
<td valign="top" align="center">0.766</td>
<td valign="top" align="center">155.08 &#xb1; 53.08</td>
<td valign="top" align="center">89.97 &#xb1; 22.51</td>
<td valign="top" align="center">0.281</td>
<td valign="top" align="center">90.03 &#xb1; 11.84</td>
<td valign="top" align="center">118.27 &#xb1; 18.23</td>
<td valign="top" align="center">0.198</td>
<td valign="top" align="center">130.42 &#xb1; 15.92</td>
<td valign="top" align="center">127.63 &#xb1; 17.70</td>
<td valign="top" align="center">0.907</td>
<td valign="top" align="center">99.69 &#xb1; 31.96</td>
<td valign="top" align="center">94.26 &#xb1; 31.85</td>
<td valign="top" align="center">0.906</td>
<td valign="top" align="center">90.99 &#xb1; 10.67</td>
<td valign="top" align="center">122.93 &#xb1; 20.61</td>
<td valign="top" align="center">0.176</td>
<td valign="top" align="center">39</td>
</tr>
<tr>
<td valign="top" align="left">Progressive motility (%), mean &#xb1; SE</td>
<td valign="top" align="center">34.70 &#xb1; 7.20</td>
<td valign="top" align="center">38.68 &#xb1; 6.30</td>
<td valign="top" align="center">0.700</td>
<td valign="top" align="center">29.88 &#xb1; 5.17</td>
<td valign="top" align="center">35.65 &#xb1; 5.42</td>
<td valign="top" align="center">0.451</td>
<td valign="top" align="center">31.50 &#xb1; 2.80</td>
<td valign="top" align="center">36.77 &#xb1; 3.08</td>
<td valign="top" align="center">0.210</td>
<td valign="top" align="center">38.99 &#xb1; 2.06</td>
<td valign="top" align="center">35.99 &#xb1; 2.07</td>
<td valign="top" align="center">0.304</td>
<td valign="top" align="center">29.28 &#xb1; 4.16</td>
<td valign="top" align="center">36.19 &#xb1; 5.58</td>
<td valign="top" align="center">0.342</td>
<td valign="top" align="center">35.41 &#xb1; 2.68</td>
<td valign="top" align="center">42.56 &#xb1; 2.87</td>
<td valign="top" align="center">0.074</td>
<td valign="top" align="center">32</td>
</tr>
<tr>
<td valign="top" align="left">Total motility (%), mean &#xb1; SE</td>
<td valign="top" align="center">49.96 &#xb1; 8.90</td>
<td valign="top" align="center">56.11 &#xb1; 9.42</td>
<td valign="top" align="center">0.660</td>
<td valign="top" align="center">54.28 &#xb1; 8.92</td>
<td valign="top" align="center">53.68 &#xb1; 8.55</td>
<td valign="top" align="center">0.961</td>
<td valign="top" align="center">42.49 &#xb1; 3.38</td>
<td valign="top" align="center">45.61 &#xb1; 3.53</td>
<td valign="top" align="center">0.526</td>
<td valign="top" align="center">58.62 &#xb1; 2.51</td>
<td valign="top" align="center">46.90 &#xb1; 2.40</td>
<td valign="top" align="center">0.001</td>
<td valign="top" align="center">48.15 &#xb1; 7.21</td>
<td valign="top" align="center">46.23 &#xb1; 7.49</td>
<td valign="top" align="center">0.856</td>
<td valign="top" align="center">52.45 &#xb1; 3.31</td>
<td valign="top" align="center">54.23 &#xb1; 3.54</td>
<td valign="top" align="center">0.715</td>
<td valign="top" align="center">40</td>
</tr>
<tr>
<td valign="top" align="left">Normal forms (%), mean &#xb1; SE</td>
<td valign="top" align="center">3.08 &#xb1; 0.03</td>
<td valign="top" align="center">3.10 &#xb1; 0.04</td>
<td valign="top" align="center">0.688</td>
<td valign="top" align="center">3.35 &#xb1; 0.34</td>
<td valign="top" align="center">3.60 &#xb1; 0.52</td>
<td valign="top" align="center">0.698</td>
<td valign="top" align="center">3.22 &#xb1; 0.16</td>
<td valign="top" align="center">3.27 &#xb1; 0.16</td>
<td valign="top" align="center">0.839</td>
<td valign="top" align="center">3.33 &#xb1; 0.10</td>
<td valign="top" align="center">3.22 &#xb1; 0.12</td>
<td valign="top" align="center">0.502</td>
<td valign="top" align="center">3.38 &#xb1; 0.39</td>
<td valign="top" align="center">3.68 &#xb1; 0.27</td>
<td valign="top" align="center">0.533</td>
<td valign="top" align="center">3.40 &#xb1; 0.12</td>
<td valign="top" align="center">3.63 &#xb1; 0.24</td>
<td valign="top" align="center">0.398</td>
<td valign="top" align="center">4</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>BMI, body mass index; &#x2013;, not applicable; WHO, World Health Organization.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="s4" sec-type="discussion">
<label>4</label>
<title>Discussion</title>
<p>In this study, we comprehensively investigated potential adverse effects of inactivated COVID-19 vaccination on male fertility. Compared to other studies (<xref ref-type="bibr" rid="B14">14</xref>, <xref ref-type="bibr" rid="B19">19</xref>, <xref ref-type="bibr" rid="B23">23</xref>), our study included booster dose and combinations of different doses of vaccines. We found that there were no changes in most semen parameters in males before and after receiving any dose or doses. Moreover, no significant differences in sex hormone levels were observed between vaccinated and unvaccinated subjects.</p>
<p>Sperm parameter analysis is viewed as one of the most fundamental and significant tools for assessing male fertility. In a study carried out by Edimiris et&#xa0;al., no significant short-term changes in ejaculate parameters were reported before and after viral vector vaccination (<xref ref-type="bibr" rid="B24">24</xref>). Likewise, Karavani et&#xa0;al. found that the mRNA vaccine did not negatively affect any of the sperm parameters over a relatively long-time period of 6&#x2013;14 months from vaccination, even in men with male factor infertility (<xref ref-type="bibr" rid="B25">25</xref>). However, in our study, a slight decrease was demonstrated in sperm total motility after completion of two doses of the vaccine when compared to samples obtained before vaccination (group D1 in <xref ref-type="table" rid="T2">
<bold>Table&#xa0;2</bold>
</xref>). The particularity with semen analysis was that we expected differences between the same individual providing two samples regardless of any intervention or treatment. There were also factors related to medical staff performance and the collection of the whole ejaculate by participants. More importantly, although the total motility decreased after the second vaccination, it remained higher than the WHO 5th percentile (46.90% <italic>vs</italic>. 40%) (<xref ref-type="bibr" rid="B22">22</xref>). Therefore, it is reasonable to infer that vaccination is safe with no apparent deleterious effect on semen parameters.</p>
<p>In fact, most of the concerns about the vaccine causing damage to male fertility stem from reports of the impact of COVID-19 on the reproductive system (<xref ref-type="bibr" rid="B14">14</xref>). Patients with severe, mild, or even asymptomatic COVID-19 were found to have abnormal semen parameters, as indicated by a decrease in semen volume, sperm concentration, total motility and progressive motility (<xref ref-type="bibr" rid="B26">26</xref>&#x2013;<xref ref-type="bibr" rid="B31">31</xref>). It is worth noting that the total sperm count after a 90-day recovery period was still significantly below that of healthy controls (<xref ref-type="bibr" rid="B32">32</xref>). In addition to the effect on semen parameters, COVID-19 is associated with other male reproductive complications, such as the development of orchitis and erectile dysfunction (<xref ref-type="bibr" rid="B33">33</xref>, <xref ref-type="bibr" rid="B34">34</xref>). Almost 10% to 23% of men diagnosed with acute SARS-CoV-2 infection developed orchitis or epididymo-orchitis (<xref ref-type="bibr" rid="B33">33</xref>, <xref ref-type="bibr" rid="B35">35</xref>, <xref ref-type="bibr" rid="B36">36</xref>). Notably, a cross-sectional study found that the prevalence of epididymitis was still as high as 42.3% among mild to moderate COVID-19 patients without testicular complaints (<xref ref-type="bibr" rid="B37">37</xref>). The histopathological findings showed Sertoli cell swelling and detachment, disfunction or reduction of Leydig cells, inflammatory infiltrations and accumulation of immunoglobulin G (<xref ref-type="bibr" rid="B29">29</xref>, <xref ref-type="bibr" rid="B38">38</xref>, <xref ref-type="bibr" rid="B39">39</xref>). In addition, Duarte-Neto et&#xa0;al. reported other testicular histological changes including vascular changes (endothelial edema, thrombosis), thickening of the tubular basal membrane and decreased spermatogenesis (<xref ref-type="bibr" rid="B40">40</xref>). Compared to pre-COVID-19 period, there were significant decreases in the International Index of Erectile Function score, sexual desire, intercourse satisfaction, orgasmic function, and frequency of sexual intercourse of the patients (<xref ref-type="bibr" rid="B41">41</xref>). Moreover, some of the recovered patients at 80 days were still diagnosed as erectile dysfunction along with psychological distress (<xref ref-type="bibr" rid="B42">42</xref>). The levels of sex hormones are also affected by SARS-CoV-2 infection. The SARS-CoV-2 nucleocapsid (N) protein, which has 90% amino acid homology with SARS-CoV N protein, is highly likely to be recognized by human immune responses (<xref ref-type="bibr" rid="B43">43</xref>). In an experimental study, Carrasco et&#xa0;al. found that the serum T levels in rats inoculated with the isolated N protein were significantly lower than those in the control group (<xref ref-type="bibr" rid="B44">44</xref>). Compared to healthy men, COVID-19 patients were accompanied by elevated serum LH levels and reduced T/LH ratios, suggesting possible subclinical impairment of male gonadal function (<xref ref-type="bibr" rid="B45">45</xref>, <xref ref-type="bibr" rid="B46">46</xref>). These injuries could be attributed to several biological mechanisms. First, SARS-CoV-2 infection could induce the up-regulation of pro-inflammatory cytokine (e.g. IL-1b, IL-6 and TNF-&#x3b1;) and down-regulation of junctional proteins (e.g. occludin, claudin and connexin-43), resulting in a disruption of blood-testis barrier (<xref ref-type="bibr" rid="B47">47</xref>). Second, fever has been reported as one of the major symptoms in patients with COVID-19 (<xref ref-type="bibr" rid="B48">48</xref>, <xref ref-type="bibr" rid="B49">49</xref>). In a meta-analysis of 67 studies and 8302 patients, above-normal body temperature was observed in 69% of positive cases (<xref ref-type="bibr" rid="B50">50</xref>). As we all know, temperature is crucial to the growth and development of cells. Under normal circumstances, the ideal temperature of sperm survival cannot be higher than 35&#xb0;C, which is 2&#xb0;C below the normal body temperature (<xref ref-type="bibr" rid="B51">51</xref>). When the human body is in a prolonged state of high fever, changes in testicular temperature occur, causing spermatogenesis to be impaired (<xref ref-type="bibr" rid="B52">52</xref>, <xref ref-type="bibr" rid="B53">53</xref>). Third, a study of oxidative and antioxidative parameters of the seminal plasma suggested that infection significantly augmented oxidative stress (OS) responses and impaired antioxidant defense machinery, leading to enhanced reactive oxygen species (ROS) production and decreased levels of superoxide dismutase activity (<xref ref-type="bibr" rid="B54">54</xref>). At normal physiological levels, ROS mediates essential physiological mechanisms such as sperm maturation, capacitation, as well as fertilization (<xref ref-type="bibr" rid="B55">55</xref>). However, its excessive production and subsequent OS in male gonads have been proven to cause lipid peroxidation of sperm membranes and intracellular oxidative damage to spermatozoa, especially sperm DNA fragmentation (<xref ref-type="bibr" rid="B55">55</xref>, <xref ref-type="bibr" rid="B56">56</xref>).</p>
<p>As mentioned earlier, the inactivated vaccine is produced in African green monkey kidney cells (Vero cells) that have been inoculated with SARS-CoV-2, then chemically inactivated using &#x3b2;-propiolactone and finally absorbed onto aluminum hydroxide (<xref ref-type="bibr" rid="B57">57</xref>). Thus, the degree of inflammation caused by it is much less than that results from infection. For example, a study confirmed elevated levels of both pro- and anti-inflammatory cytokines (including IFN-&#x3b3;, IL-1ra, IL-10, IL-18, MCP-3, M-CSF and G-CSF) in COVID-19 patients, while no changes in various cytokines (including T helper 2 cell-related cytokines IL-4, IL-5, and IL-10) or lymphocyte subset distribution before and after vaccination were observed (<xref ref-type="bibr" rid="B58">58</xref>, <xref ref-type="bibr" rid="B59">59</xref>). In addition, there are concerns that adverse reactions to inactivated vaccine may also affect fertility, especially fever. Fortunately, unlike the higher fever rate caused by infection, the percentage after vaccination did not exceed 5% in several evaluations. Most of the participants reported mild or moderate fever that was transient or resolved in few days (<xref ref-type="bibr" rid="B58">58</xref>, <xref ref-type="bibr" rid="B60">60</xref>&#x2013;<xref ref-type="bibr" rid="B62">62</xref>). Therefore, it is easy to understand that inactivated SARS-CoV-2 vaccination has no effect on sperm parameters.</p>
<p>This study has several limitations. First, the data from all participants were collected in a single center, thereby limiting the diversity of individuals studied. Second, this study did not evaluate male reproductive potential, i.e. comparing the results of assisted reproductive technologies cycles before and after vaccination. Third, the majority of population included in our study was men planning to conceive, which limited the generalizability of the conclusions.</p>
</sec>
<sec id="s5" sec-type="conclusions">
<label>5</label>
<title>Conclusion</title>
<p>Although there have been several studies on the impact of a single dose of inactivated SARS-CoV-2 vaccine on male reproductive capacity, this is the first time to comprehensively evaluate the effects of combination of different doses. Most sex hormone values remained unchanged after vaccination. However, the FSH and PRL levels in the one-dose vaccinated group were higher than other groups which may relate to its small sample size. The majority of semen parameters also showed similar results. Although the total motility decreased following two-dose vaccination compared to before vaccination, it was still within normal range. Accordingly, we are confident in suggesting that vaccination is safe with no adverse effect on male reproductive ability. Our result can be used to serve as a consulting tool for clinical doctors and reassure men who have already vaccinated to conceive. Future multicenter studies should be conducted to verify the generalizability of the research results and continue to monitor the long-term effects of vaccines on male health and sexual function.</p>
</sec>
<sec id="s6" sec-type="data-availability">
<title>Data availability statement</title>
<p>The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.</p>
</sec>
<sec id="s7" sec-type="ethics-statement">
<title>Ethics statement</title>
<p>The studies involving humans were approved by Ethics Committee of the Affiliated Hospital of Jining Medical University. 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.</p>
</sec>
<sec id="s8" sec-type="author-contributions">
<title>Author contributions</title>
<p>YD: Conceptualization, Formal analysis, Investigation, Methodology, Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. ZB: Conceptualization, Formal analysis, Investigation, Methodology, Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. YQ: Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. JM: Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. YL: Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. YZ: Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. AY: Conceptualization, Formal analysis, Investigation, Methodology, Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. FC: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Writing &#x2013; original draft, Writing &#x2013; review &amp; editing.</p>
</sec>
</body>
<back>
<sec id="s9" sec-type="funding-information">
<title>Funding</title>
<p>The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was funded by the Natural Science Foundation of Shandong Province (grant no. ZR2020QC100).</p>
</sec>
<ack>
<title>Acknowledgments</title>
<p>We express our gratitude to all working staff at the Center for Reproductive Medicine of the Affiliated Hospital of Jining Medical University and participants in this study.</p>
</ack>
<sec id="s10" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>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.</p>
</sec>
<sec id="s11" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
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