Journal of Vaccine Research 2024, Vol.14, No.5, 255-268 http://medscipublisher.com/index.php/jvr 263 pruritus (Mittendorf et al., 2019). These findings are consistent with other studies that have evaluated the safety of cancer vaccines in breast cancer patients, indicating that these vaccines are generally well-tolerated with manageable side effects (Hosseini et al., 2023; Dafni et al., 2020; Singer et al., 2020). 6.2 Long-term safety data Long-term safety data for cancer vaccines in breast cancer patients are encouraging. The E75 vaccine has shown sustained safety over a median follow-up period of 60 months. Booster inoculations, administered every six months after the primary vaccine series, were also well-tolerated, with only grade 1 and 2 local and systemic toxicities reported. Notably, delayed urticarial reactions were observed in 13% of boosted patients, but these were grade 2 and well-tolerated. Another study on a plasmid DNA vaccine encoding the ERBB2 intracellular domain reported that the majority of vaccine-related toxic effects were grade 1 and 2, with no significant differences between dose arms. Long-term follow-up indicated that the vaccine was safe, with no severe adverse events reported. These findings are corroborated by a systematic review and meta-analysis, which found that therapeutic cancer vaccines generally display low toxicity, even over extended periods (Dafni et al., 2020). Overall, the long-term safety profile of cancer vaccines in breast cancer patients appears to be favorable, with most adverse events being mild to moderate in severity (Hosseini et al., 2023; Mittendorf et al., 2019; Singer et al., 2020). 6.3 Risk of immune-related adverse events The risk of immune-related adverse events (irAEs) associated with cancer vaccines is an important consideration. While most cancer vaccines have been shown to be safe, there is a potential for irAEs, particularly when used in combination with other immunotherapies such as immune checkpoint inhibitors (ICIs). A systematic review and meta-analysis on the safety of influenza vaccination in cancer patients treated with ICIs found that the incidence of irAEs was not significantly increased following vaccination. However, another study highlighted that late-onset and long-lasting irAEs are common but often underreported. This study emphasized the need for long-term monitoring to fully capture and characterize these events (Ghisoni et al., 2021). In the context of cancer vaccines, the E75 vaccine study reported delayed urticarial reactions in a subset of patients, indicating a potential for irAEs (Vreeland et al., 2011). Similarly, the NP-S vaccine study noted that while most adverse events were mild, there was a need for ongoing surveillance to monitor for any late-onset irAEs (Mittendorf et al., 2019). These findings underscore the importance of vigilant monitoring and reporting of irAEs to ensure the long-term safety of cancer vaccines in breast cancer patients. 7 Challenges in Sustaining Long-Term Immunity 7.1 Waning immunity Waning immunity is a significant challenge in the context of long-term immunological effects of cancer vaccines in breast cancer patients. Over time, the immune response elicited by a vaccine can diminish, leading to a reduced ability to recognize and combat cancer cells. This phenomenon has been observed in various vaccine studies, including those targeting HER-2/neu in breast cancer. For instance, a study demonstrated that HER-2/neu peptide-specific CD8+ T-cell responses were short-lived, with a noticeable decline in immune response five months post-vaccination . This waning immunity can be attributed to several factors, including the nature of the antigen, the adjuvant used, and the patient's immune status. Moreover, the tumor microenvironment (TME) plays a crucial role in the persistence of immune responses. The TME can exert immunosuppressive effects that hinder the long-term efficacy of cancer vaccines. For example, the presence of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) within the TME can suppress the activity of effector T cells, leading to a decline in vaccine-induced immunity. Additionally, the continuous exposure to tumor antigens without adequate immune stimulation can lead to T-cell exhaustion, further contributing to the waning of immunity. To address this challenge, combination therapies that include immune checkpoint inhibitors (ICIs) have shown
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