In a recent study published in the journal Annals of Internal Medicine, researchers investigated whether short-term adverse effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger ribonucleic acid (mRNA) vaccinations are related to neutralizing antibody (nAB) responses.

COVID-19 Vaccine Side Effects and Long-Term Neutralizing Antibody Response: A Prospective Cohort Study. Image Credit: peterschreiber.media / Shutterstock

Background

SARS-CoV-2 vaccinations lower related infections, hospital admissions, and deaths; however, protection wanes with time despite booster doses. Booster vaccine uptake has been poor, with typical reasons including a perceived lack of additional benefit, a prior history of SARS-CoV-2 infections or vaccinations, and concerns regarding adverse effects. Recent data shows that more systemic symptoms post-vaccination may indicate a robust immune response. Population health messaging may aid adoption by portraying transient vaccination-related symptomatology as positive vaccine efficacy indicators.

Quantifying nAB activity is crucial since SARS-CoV-2 vaccinations have distinct effects on neutralizing antibodies, and anti-SARS-CoV-2 spike protein immunoglobulin G (anti-S IgG) and nABs are essential for protection against coronavirus disease 2019 (COVID-19). Providing nABs to animals has protected them against infection despite SARS-CoV-2 exposure in high doses. In a human trial, nAB titers mediated above two-thirds of vaccination effectiveness.

About the study

In the present prospective cohort study, researchers evaluated the impact of short-term adverse effects of COVID-19 vaccinations on functional antibody titers one and six months after vaccination.

The study included Building Optimal Antibodies Study participants aged above 18 years without SARS-CoV-2 exposure or a history of immunological disorders or medications such as steroids or immunomodulators. The participants, recruited through newsletters mailed to California University staff and patients and via conventional and social media, received two mRNA-1273 or BNT162b2 vaccinations. The researchers determined COVID-19 history based on IgG titers against SARS-CoV-2 spike protein at study initiation and nucleocapsid (N) proteins at six months, excluding those with positive results and those who received Ad26.COV2.S vaccination doses.

The researchers collected blood samples from the study participants before they received COVID-19 vaccines and again one month and six months after prime vaccination with mRNA-1273 or BNT162b2 to measure nAB titers by pseudovirus assays. They expressed nAB titers as the median inhibitory dose (ID⁵⁰).

Participants also completed symptom surveys and biometric measurements after every vaccination to determine nAb response predictors. Physical symptoms included headache, fever, tiredness, chills, feeling unwell, muscle pain, joint pain, nausea, vomiting, pain at the site of injection, swelling, redness, swollen or tender lymph nodes, swelling or pain in the non-vaccine-receiving arm, stomach aches, and allergic reactions (breathing difficulty, swelling of the face or throat, and rashes).

Self-documented variables included the absence or presence of 13 vaccination-related symptoms and the total symptom count. Biometric measures included vaccination-related alterations in heart rate (HR), skin temperature (ST), respiratory rate (RR), and heart rate variability (HRV). The researchers performed mixed-effects modeling for analysis, adjusting for age, biological sex, body mass index, and smoking status.

Results

The symptomatology analyses included 363 individuals (mean age, 52 years; 66% female), and the biometric-related analyses included 147 (mean age, 59 years; 66% female). Chills (1.6-times higher ID⁵⁰), tiredness (1.5-times higher ID⁵⁰), feeling unwell (1.5-times higher ID⁵⁰), and headache (1.4-times higher ID⁵⁰) after the second vaccination were associated with higher neutralizing antibody responses one month and six months after mRNA-1273 or BNT162b2 vaccinations.

Symptom count (1.1 times higher ID⁵⁰ per additional vaccination-related symptom) and vaccination-induced alterations in heart rate and skin temperature showed positive associations with neutralizing antibody responses one- and six months post-vaccination. Every degree Celsius ST elevation after the second vaccination was associated with two-fold higher neutralizing antibody titers a month later and three-fold higher titers after six months. For every ten beats per minute rise in HR after the second dose, ID⁵⁰ values showed a 1.5-fold increase across both time points.

Conclusions

The study findings showed that the short-term systemic adverse effects of SARS-CoV-2 mRNA vaccination are associated with longer-lasting neutralizing antibody responses. The findings may help alleviate unfavorable attitudes regarding vaccination side effects, which might impede vaccine uptake. Individuals who reported chills, weariness, feeling unwell, or headaches following the second dose of the vaccination had 1.4 to 1.6 times the nAB level as those who did not report any symptoms one month and six months later.

Each new symptom reported after dose 2 indicated a 1.1-fold increase in subsequent nABs. Higher vaccination-induced change in ST and HR, particularly after the second dose, predicted higher nAB one month and six months later. However, the researchers conducted the study in 2021 on individuals receiving the primary vaccine series, making the generalizability of the findings unclear.