Impact of sex and age on vaccine-related side effects and their … – Nature.com

This study systematically investigated the impact of sex and age on the side effects following the third vaccine dose in a cohort of COVID-19 mRNA vaccinated adults. Here, using cross-sectional and longitudinal analyses, we identified significantly higher frequency of several vaccine-related adverse symptoms and prolonged recovery rate in females and younger adults following the third vs second vaccine doses. Additionally, we found several individual side effects that significantly contributed to the duration of side effects.

Our findings of higher frequencies of COVID-19 vaccine-related side effects among females and younger adults compared to males and elderly adults were consistent with previous reports6,7,11,12,13. Additionally, our longitudinal analyses revealed worse outcomes with longer recovery from side effects in females and younger adults compared to those in males and elderly adults. Other studies reported sex differences in vaccine response and higher vaccine efficacy but worse adverse reactions in females vs males, including vaccines against influenza, hepatitis B and yellow fever14,15,16. Higher number of B cells resulting in greater antibody production in females17 and increased stimulation of immune cells by female sex hormones (estrogen, progesterone), as well as suppression by male sex hormones (testosterone) may be considered a plausible mechanism of sex differences in responses to vaccines18,19.

In terms of adverse age-related impact on the frequency and duration of side effects following vaccine, decline in immune function with age, referred to as immunosenescence, should be considered20,21. Effect of immunosenescence on decline of vaccine efficacy was reported with other vaccines such as influenza, varicella zoster, and the combination vaccine against tetanus, diphtheria, and pertussis22,23,24. Our findings of higher number and longer duration of side effects among younger adults support these data.

Axillary pain is a side effect that occurred at a significantly higher frequency following the third vaccine dose compared to the first or second vaccine doses. After the first and second doses in the BNT162b2 trial, axillary swelling was recorded as an unsolicited reaction only25. In the mRNA-1273 trial, axillary swelling and tenderness were reported in 11.6% patients after the first vaccine dose and in 16% after the second vaccine dose26. In our previous study of BNT162b2 and related side effects, frequency of axillary lymph node swelling or axillary pain was 0% (0/262) after the first vaccine dose, 3.9% (10/257) of lymph node swelling after the second vaccine dose27, and 15% (41/272) of axillary pain in this third vaccine dose study. Ipsilateral vaccine-related reactive axillary lymphadenopathy was demonstrated in multiple radiologic studies, such as screening mammograms28,29,30 or cancer surveillance PET CT studies. Asymmetric axillary lymphadenopathy is a concerning imaging finding for radiologists since the differential diagnosis includes nodal metastatic disease31. These notions underscore the importance of obtaining COVID-19 vaccination history prior to image examinations.

Several symptoms were identified as the culprit symptoms contributing to the prolonged duration of side effects following the third vs second vaccine doses, specifically joint pain after the third vaccine dose, and asthma, ear fullness, and bleeding at the injection site after the second vaccine dose. A possible mechanism could be related to previous studies of mRNA COVID-19 vaccine32 and influenza vaccines33,34,35, which reported an increase of proinflammatory cytokines such as TNF- and IL-6, and a decrease of extracellular vesicle immune-regulatory microRNA levels following vaccination. Levels of these proinflammatory cytokines and extracellular vesicle microRNA may stimulate systemic side effects following the third vaccine dose mRNA vaccine, which we describe in this study.

On the other hand, asthma and ear fullness after the second vaccine dose were identified as significant symptoms prolonging the duration of side effects after the second vs third vaccine doses. Notably, asthma and ear fullness are allergic symptoms which had already been present in the individuals prior to vaccination and were exacerbated by the vaccine. Previously reported systemic immune response syndrome (SIRS)36,37 and its association with upregulation of genes involved in neutrophil degranulation and cytokine signaling38 may be considered as a potential mechanism of our findings. These notions underscore the importance of obtaining a thorough history about an individuals past medical diagnoses or treatments prior to vaccination.

Bleeding at the injection site after the second vaccine dose was also identified as one of culprit symptoms prolonging the duration of side effects following the second vaccine dose. This local dermatological symptom is known as COVID arm8,27. Delayed hypersensitivity reaction by type IV allergic response was proposed as the mechanism9,10.

Our findings about the different individual symptoms affecting the duration and severity of the vaccine-related side effects suggest that immune responses that generate the side effects differ between the third vaccine dose (systemic inflammation) and second vaccine dose (type I and IV allergic responses). Further immunological studies including cytokine and antibody level measurements would be warranted, and these findings would contribute for the understanding of mechanism of mRNA vaccine-related side effects.

As a limitation of this study, a small number of subjects for the vaccine-related side effect study, with discrepancies in sex and age distribution, were considered. Since the subjects in this study were derived from healthcare workers, distribution discrepancies with more females and younger adults occurred. For further analyses, a larger number of subjects with an equal distribution of sex and age should be considered. With regard to the subjects, while all of the subjects in this study had no history of COVID-19 diagnosis prior to vaccination, the inclusion of asymptomatic cases among them was considered another limitation of this study. In a study involving the Japanese population, the frequency of asymptomatic cases was 0.33% out of one million tested individuals in 202139, and 1.1% (23 out of 2185) among healthcare workers40. Considering the higher frequency of vaccine-related side effects among subjects with a past history of COVID-19 infection compared to those without such a history41,42, the detection and exclusion of asymptomatic cases through anti-COVID-19 IgG measurement would be warranted for further analyses.

In conclusion, this study investigated the impact of sex and age on mRNA COVID-19 vaccine-related side effects in booster-vaccinated adults (i.e. adults who received the third vaccine dose). We found that vaccine-related side effects are more frequent among females and younger adults, and that these two groups have a prolonged recovery compared to males and elderly adults. We also identified the individual culprit side effects that influence the duration of vaccine-related adverse effects following the third vs second dose. Specifically, we identified the significant negative contribution of systemic symptoms such as joint pain and headache after the third vaccine dose, and exacerbation of an underlying allergic condition and type IV allergic response after the second vaccine dose. Identification of the unique sex- and age-specific adverse symptoms, as well specific side effects characteristic of third and second COVID-19 vaccine doses will provide an opportunity to better understand the nature of sex- and age-associated immunological differences and develop safer and more efficacious vaccines.

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