key: cord-0789584-t46yayjp
authors: Tissot, Noémie; Brunel, Anne-Sophie; Bozon, Fabienne; Rosolen, Béatrice; Chirouze, Catherine; Bouiller, Kevin
title: Patients with history of covid-19 had more side effects after the first dose of covid-19 vaccine
date: 2021-07-22
journal: Vaccine
DOI: 10.1016/j.vaccine.2021.07.047
sha: f6c0fa7f384742dadcf2d783b2291b3cf61b1c76
doc_id: 789584
cord_uid: t46yayjp

INTRODUCTION: COVID-19 vaccination seems to be the most pertinent pharmacologic public health measure to control the pandemic. Reactogenicity symptoms were frequent in vaccine recipients mostly mild to moderate and commonly reported after the second dose. However, there is a lack of data in patients with a previous diagnosis of Covid-19. METHODS: We analysed side effects of 311 patients after the first dose of Pfizer-BioNTech COVID-19 vaccine, in a french university hospital. We compared patients with COVID-19 history to naive individuals. All the data collected are based on self-reported, including COVID-19 exposure status. RESULTS: Overall, 229 (74%) patients reported at least one side effect. Among participants with history of Covid-19, 95% reported at least one adverse event versus 70% in naive patients (p<0.01). However, symptom intensity was not different between the 2 groups. CONCLUSION: Vaccine recipients with prior COVID-19 reported more, but no more serious, side effects than naive participants.

The coronavirus disease 2019 (COVID-19) pandemic continues to affect thousands people in France and is responsible, to date, for nearly 85 000 deaths. Currently, only corticosteroid and tocilizumab have so far proved to be effective in patients with severe forms of COVID-19, and vaccination seems to be the most pertinent pharmacologic public health measure to control the pandemic. The national COVID-19 vaccination program began in France at the end December 2020. Pfizer-BioNTech, an ARN vaccine, was the first recommended in France for over-50-years-old-healthcare-workers, or with high risk of severe COVID-19 and for patients over 75 years of age [1] . In phase 1/2/3 of the studies conducted by Pfizer-BioNTech, in vaccine recipients, reactogenicity symptoms were frequent, mostly mild to moderate, commonly reported after the second dose [2] [3] [4] . However, patients with a previous clinical or microbiologic diagnosis of Covid-19 were excluded.

We assessed the side effects after the first dose of Pfizer-BioNTech vaccine, comparing patients with or without history of COVID-19.

We conducted a prospective and observational, single center study in university tertiary care hospital in Besançon, France. Eligible subjects were healthcare workers vaccinated with one dose of Pfizer-BioNTech COVID-19 vaccine. From 27 January to 5 February 2021, an anonymous questionnaire was proposed on site to each participant just before the second dose of vaccine (between21 to 28 days after the first one). Data collected were subject's demographic characteristics, the occurrence and intensity of local (redness or pain at the injection site) and/or systemic symptoms (fatigue, vomiting, diarrhoea, headache, chills, fever, muscle pain, joint pain ...), and characteristics and data of prior COVID-19 disease. All the data collected in the questionnaire are based on self-reported, including COVID-19 exposure status. Our questionnaire was developed on the basis of the FDA Center for Biologics Evaluation and Research (CBER) guidelines on the toxicity classification scale for healthy adults.

Comparisons of reactogenicity symptoms frequency between naive individuals, defined as asymptomatic, COVID-antibody status unknown and participants with history of COVID-19 were performed. All variables were examined by univariate analysis using the chi-square or Fisher's exact test, as appropriate. A p-value < 0.05 was considered significant.

Ethics approval and consent to participate: According to French legislation in this period, and because no intervention was performed on patients, no written informed consent was given by the patients Our study protocol followed the ethical guidelines of the declaration of Helsinki and was approved by our institutional review board.

The questionnaire was completed by 311 of 351 healthcare workers vaccinated during the study period (response rate, 89%). . The mean age was 55.4 ± 6.4 years and participants were mostly women (60%). History of COVID-19 was reported in 20 participants (6.4%). Among them, 19 had symptomatic COVID-19 confirmed by naso-pharyngeal RT-PCR, and only one had positive serology without symptoms. None of them were hospitalised. The mean duration between COVID-19 and first dose of vaccine was 10.3 ± 2 months. Twelve of 20 (60%) participants did SARS-CoV2 serology and 8 were positive in a mean time of 8 ± 1 months before the vaccination. A total of 229 participants (74%) reported at least one side effect. Of the adverse reactions, 37% of participants reported systemic reaction (mainly fatigue (18%), headache (14%) muscle pain (20%)), and 66% reported a local event, such as pain at the site injection (63%) or erythema (8%). No side effects required additional medical attention.

Among participants with prior SARS-Cov-2 infection, 19/20 (95%) reported at least one adverse event, 18 (90%) at least one local reaction and 13 participants (65%) systemic side effects. Five participants had to lie down for 24-48 hours, and only one was granted sick leave.

There was a relationship between history of COVID-19 and reactogenicity symptoms frequency. Vaccine recipients with prior COVID 19 infection experienced systemic side effects with a significantly higher frequency than naive patients (figure 1). However, symptom intensity was not different between the 2 groups, excepted for headache (Table 1) .

We herein report a comparative study of post-vaccination adverse events between vaccine recipients with a COVID 19 pre-existing immunity and naive individuals.

Reactogenicity is a part of the safety profile evaluation of a given vaccine. It refers to the potential for expected and unexpected local or systemic adverse reactions after vaccine administration. Overall, reactogenicity events after a first dose of Pfizer-BioNTech COVID-19 vaccine were common as previously described in pharmaceutical studies conducted by Pfizer-BioNTech [3] [4] [5] . Among all studied vaccine recipients, 84.7% reported at least one local injection site event and 77.4% at least one systemic reaction [3] . Pain at the injection site, fatigue, headache and muscle pain were the most common adverse events in these studies [2] [3] [4] . Symptoms usually peak by day 2 after vaccination and resolve by day 7 [4] . In our study, the rate of reported adverse events was lower than those in the safety studies. This is probably related to the fact that this is a real-world study, patients are warned in advance of vaccine side effects, and that they are self-reported and unsolicited.

Our study showed that vaccine recipients with a COVID 19 pre-existing immunity experienced significantly more frequent reactogenicity symptoms after the first vaccine dose compared to naive individuals, especially systemic symptoms. In the Pfizer-BioNTech Phase 3 study, 1125/37586 (3%) patients had a positive serology for SARS-CoV2. Of these, 545 patients were in the vaccine group and 580 in the placebo one. Adverse events reported were no more frequent in seropositive individuals [6] .

In the last safety report of February 2021, the French National Agency for the Safety of Medicines and Health Products reported 239 cases of adverse reactions in people with a history of COVID-19 infection after the Pfizer-BioNTech vaccine [7] . The cases reported did not appear to present any specific characteristics in terms of the reported reactions severity, particularly reactogenicity. The proportion of patients who developed systemic reactogenic effects seemed higher in case of a history of COVID-19 (63.2% vs 50.8%), but with a lower severity. In contrast, in the current analyse, we did not report significant differences in severities, except for headache. This can be explained by the small sample size.

In immunogenicity trials [2, 4, 5] , the frequency and severity of reactogenicity symptoms were higher after the second dose of vaccine than the first one except for vomiting and diarrhoea, which were generally similar regardless of dose. For all age groups, fatigue, headache and new/worsened muscle pain were most common. Some recent studies have highlighted that a single dose of Pfizer-BioNTech vaccine elicited rapid immune response in vaccined individuals with pre-existing immunity, and with postvaccination antibody titers similar to or higher than those seen in naive participants who received two doses of vaccine [8] . The authors of study also suggested that the vaccine systemic reactogenicity after the first dose was more pronounced in people with pre-existing immunity and appeared to be similar to the side effects reported for the second dose in phase III vaccine trials [2] . These data, combined with current knowledge of the immunological response to SARS-Cov-2 and the phenomena of reinfection, have led to a recent modification of the vaccination strategy in France. According to the French Health Authority, people with a medical history of COVID-19 should receive only one (mRNA or adenovirus-vectored) vaccine dose except for immunocompromised patients (2 doses of vaccine) [9] . Some limitations should be highlighted. All data collected were self-reported. History of positive SARS-CoV2 serology was also self-reported. It cannot be ruled out that subjects with an asymptomatic and undocumented form of COVID-19 were erroneously included in the "naive patients" group. Furthermore, the serology alone is not a sufficient marker of protection. It only attest contact with SARS-CoV-2. Neutralizing antibodies titration may provide evidence of a protective humoral response. However, this test was not performed in our study. In addition, the small sample size of participants with a history of COVID-19 should lead to caution in interpreting the results.

To conclude, we found that vaccine recipients experienced more frequent reactogenicity after a first dose of the Pfizer-BioNTech COVID-19 vaccine compared to naive individuals.

Further studies are needed to confirm these results. 

Stratégie de vaccination contre le SARS-CoV-2 -Place du vaccin à ARNm COMIRNATY® (BNT162b2)

A PHASE 1/2/3

Reactions and Adverse Events of the Pfizer-BioNTech COVID-19 Vaccine | CDC 2021

Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Point de situation sur la surveillance des vaccins contre la COVID-19 -ANSM : Agence nationale de sécurité du médicament et des produits de santé n

Antibody Responses in Seropositive Persons after a Single Dose of SARS-CoV-2 mRNA Vaccine

Stratégie de vaccination contre le SARS-CoV-2: Vaccination des personnes ayant un antécédent de Covid-19

The authors thank Léa TISSOT for editorial assistance.

In the interest of transparency, we ask you to disclose all relationships/activities/interests listed below that are related to the content of your manuscript. "Related" means any relation with for-profit or not-for-profit third parties whose interests may be affected by the content of the manuscript. Disclosure represents a commitment to transparency and does not necessarily indicate a bias. If you are in doubt about whether to list a relationship/activity/interest, it is preferable that you do so.The following questions apply to the author's relationships/activities/interests as they relate to the current manuscript only.The author's relationships/activities/interests should be defined broadly. For example, if your manuscript pertains to the epidemiology of hypertension, you should declare all relationships with manufacturers of antihypertensive medication, even if that medication is not mentioned in the manuscript.In item #1 below, report all support for the work reported in this manuscript without time limit. For all other items, the time frame for disclosure is the past 36 months.

Time frame: Since the initial planning of the work ____None 1All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) No time limit for this item. Please place an "X" next to the following statement to indicate your agreement: X I certify that I have answered every question and have not altered the wording of any of the questions on this form.