Reactivation of Human herpesviruses (HHVs) following SARS-CoV-2 infection and vaccination: a systematic review of clinical studies

Human herpesviruses (HHVs) can establish latency and reactivate during critical illness and in the context of SARS-CoV-2 infection or vaccination. This systematic review aimed to evaluate available evidence on HHV reactivation in the setting of SARS-CoV-2 infection and vaccination. A systematic literature search was conducted across multiple databases including Web of Science, PubMed, Embase, and Scopus published from 2019 to 2025. Moreover, the quality and risk-of-bias assessments for all included studies were conducted using the Newcastle – Ottawa Scale (NOS) and the Joanna Briggs Institute (JBI) tools. HHV reactivation was frequently observed in critically ill COVID-19 patients, particularly involving Epstein – Barr virus (EBV), Herpes simplex virus type 1 (HSV-1), Cytomegalovirus (CMV), and Human herpesvirus 6 (HHV-6). Reactivation rates among reported cohorts varied, with EBV reactivation documented in approximately 65% of cases with herpesvirus reactivation and HSV-1 detectable in around 30%. Reactivation has also been documented post-vaccination, with herpes zoster and herpes simplex reactivations observed. The study revealed an association between SARS-CoV-2 infection/vaccination and HHV reactivation, especially in severe COVID-19 cases. These findings demonstrated the need for further research to clarify the clinical significance and underlying mechanisms of HHV reactivation in this context. Some viruses from the herpes family can stay inactive (asleep) in the body for many years. These include viruses that cause cold sores, shingles, and glandular fever. When the immune system is under stress, these viruses can sometimes become active again. This review examined 20 studies to understand whether these herpes viruses become active again after COVID-19 infection or after COVID-19 vaccination. Most of the studies were well designed, although some included only a small number of people. The findings showed that herpes virus reactivation mainly occurred in people with severe COVID-19, especially those who were very unwell, in intensive care, or using breathing machines. The most commonly reactivated viruses were Epstein – Barr virus and herpes simplex virus. These were linked to problems such as long-lasting tiredness, lung infections, or pneumonia. Shingles was less common and usually appeared weeks after COVID-19 infection. Another virus, cytomegalovirus, was mostly seen in very sick patients and was linked to longer hospital stays. Also, the reactivation of herpes viruses after COVID-19 vaccination was rare and usually mild. Most people recovered without treatment, and serious problems were uncommon. Overall, COVID-19 vaccines were found to be safe and may even help protect people with weaker immune systems. In summary, herpes viruses can reactivate during severe COVID-19 illness, but this is uncommon after vaccination. Understanding this can help patients and healthcare workers to recognize and manage symptoms early.