Identifying and testing people likely to have SARS-CoV-2 is essential for infection control, including post-vaccination. Vaccination is an important public health strategy to reduce SARS-CoV-2 infection globally.
Some people experience systemic symptoms after vaccination, which overlap with COVID-19 symptoms. This study compared early post-vaccination symptoms in people who subsequently tested positive or negative for SARS-CoV-2, using data from the COVID Symptom Study (CSS) app.
Preventing the spread of SARS-CoV-2 requires rapid recognition followed by quarantine of infected individuals (along with appropriate medical care). However, there is an overlap between COVID-19 symptoms and early systemic symptoms following vaccination.
Furthermore, immunity to SARS-CoV-2 does not occur immediately after vaccination, with functional protection from approximately day 12. Quarantining and testing every individual with systemic symptoms early after vaccination would be burdensome, expensive, and laborious. , but given the impact of viral outbreaks it could be inevitable if SARS-CoV-2 infection cannot be definitively excluded.
Here we aim to determine if symptom profiles can be used to differentiate individuals with systemic side effects from vaccination alone from individuals with overlapping SARS-COV-2 infection.
Methods
We conducted a prospective observational study in 1,072,313 UK CSS participants who were asymptomatic when vaccinated with the Pfizer-BioNTech mRNA vaccine (BNT162b2) or the Oxford-AstraZeneca adenovirus vector vaccine (ChAdOx1 nCoV-19) between on December 8, 2020 and May 17, 2021, who subsequently reported symptoms within seven days (N = 362,770) (other than local symptoms at the injection site) and were tested for SARS-CoV-2 ( N = 14,842), with the aim of differentiating the side effects of vaccination based on superimposed SARS-CoV-2 infection.
Participants simultaneously recorded post-vaccination symptoms and SARS-CoV-2 test results.
Demographic and clinical information (including comorbidities) was recorded. Symptom profiles in people who tested positive were compared to a 1:1 matched population who tested negative, including using machine learning and multiple models taking into account UK testing criteria.
Results
Differentiating post-vaccination side effects from early COVID-19 symptoms was challenging, with sensitivity in identifying individuals who tested positive being 0.6 at best.
Most of these people did not have fever, persistent cough or anosmia/dysosmia, symptoms required to access UK testing; and many only had systemic symptoms commonly seen after vaccination in SARS-CoV-2-negative individuals (headache, myalgia, and fatigue).
Figure: Disease profiles in symptomatic individuals after early vaccination, comparing symptom prevalence (symptom reported at any time during the first week) in positive versus negative cases (population matched 1:1; N = 145 for each). * p < 0.05 ** p < 0.01.
Interpretation Post-vaccination symptoms per se cannot be differentiated from COVID-19 with clinical robustness, either using symptom profiles or computationally derived models. People who develop systemic symptoms after vaccination should be tested for SARS-CoV-2 or quarantine to prevent community spread. |
Research in context
Evidence before this study
There are multiple surveillance platforms internationally that ask about COVID-19 and/or post-vaccination side effects. We designed a study to examine differences between vaccination side effects and early symptoms of COVID-19.
We searched PubMed for peer-reviewed articles published between January 1, 2020 and June 21, 2021, using keywords: “COVID-19” AND “Vaccination” AND (“mobile app” OR “web tool” OR "digital survey" OR "early detection" OR "Self-reported symptoms" OR "side effects").
Of 185 results, 25 studies attempted to differentiate COVID-19 symptoms versus post-vaccination side effects; however, none used artificial intelligence (AI) technologies (“machine learning”) in conjunction with real-time data collection that also included comprehensive and systematic symptom assessment. Furthermore, none of these studies attempted to discriminate early signs of infection from vaccination side effects (specifically here: Pfizer-BioNTech mRNA vaccine (BNT162b2) and Oxford-AstraZeneca adenovirus vector vaccine (ChAdOx1 nCoV-19)). . Furthermore, none of these studies sought to provide comparisons with current testing criteria used by health services.
Added value of this study
This study, in a large community-based cohort, uses prospective data capture in a novel effort to identify individuals with COVID-19 in the immediate post-vaccination period.
Our results suggest that the early symptoms of SARS-CoV-2 cannot be robustly differentiated from the side effects of vaccination.
Implications of all available evidence
Our study suggests that post-vaccination symptoms per se cannot be clinically differentiated from COVID-19 and therefore people who present with systemic symptoms after vaccination should be tested for SARS-CoV-2. 2 to prevent spread in the community.
Discussion
We were unable to robustly differentiate post-vaccination symptoms per se from SARS-CoV-2 infection overlap.
Here we aimed to develop a clinically useful algorithm that predicts SARS-CoV-2 infection early after vaccination, analyzing symptoms according to the proven infection status in symptomatic individuals. Such an algorithm would be extremely useful, particularly in countries with limited health resources, as testing could be targeted at those predicted to be positive, with these individuals quarantined until a result is available. To our knowledge, this is the first study with this objective.
However, we were unable to robustly differentiate post-vaccination symptoms per se from overlapping SARS-CoV-2 infection.
Although one-third of the million vaccinated app users reported symptoms previously associated with COVID-19 after early vaccination, only 4% of symptomatic people reported testing for SARS-CoV-2 even if access was allowed late for testing. Taking into account people who reported that at least one of the symptoms met the NHS criteria for testing (266,502 overall), 40% (107,929) were tested.
During the study period, testing became widely available in the UK and it is unclear why more symptomatic people (including those with the widely advertised core symptoms of fever, persistent cough and anosmia/dysosmia) were not tested. Possible reasons for not testing, even among people presenting with any of the main symptoms, include lack of knowledge about when and where to test, as well as the absence of severe and/or multiple symptoms.
Additionally, there is currently no specific guidance being provided to vaccine recipients, either highlighting the possibility of post-vaccination infection or on when to access testing in the post-vaccine period, which could also affect the decision to test among vaccinated people. By contrast, of 149 people who tested positive, only 62 (41%) had symptoms that met the current UK testing criteria. We do not know why the other 88 positive people were tested (e.g., contact tracing, routine workplace testing, direct personal request via app).
Our data also suggest that the sensitivity of using core symptoms to justify COVID-19 testing may be lower after vaccination than in pre-vaccination times (here 48%, previously 73%). Although people with core symptoms were more likely to test positive than those without, the overall sensitivity and AUC suggest that the current UK testing policy is not optimal for managing a pandemic, especially now that rapid testing capacity is much greater than when these criteria were established. In particular, the UK’s current testing criteria are more limited than the WHO guidelines and those of many other jurisdictions of similar GDP (including France, Germany, the US and Australia).
Although there were some differences in the prevalence and distribution of symptoms between positive and negative individuals, they could not be robustly used to discriminate between groups, including using machine learning. We also considered time to symptom onset and duration of symptoms after vaccination (previous trials and post-marketing observational data have examined these parameters, but not with respect to SARS-CoV-2 status).
Whether positive or negative, the median peak symptom burden was on day 3 in both groups, consistent with previously reported vaccination side effect profiles. As time went on, some symptoms seemed to become more common only in the positive group (e.g., persistent cough, hoarse voice), the timing of which coincides with the serial interval and incubation period of SARS-CoV-2. Please note that no formal statistical analyzes were performed on this point, and the results regarding duration of symptoms are only descriptive.
Future work should evaluate statistical differences in symptom duration for the two groups, in larger cohorts. However, the critical public health importance of identifying and isolating cases early, and the lack of clear differences between infected and uninfected symptomatic individuals, does not allow the luxury of a watch-and-wait approach.
Conclusions
- In conclusion, post-vaccination symptoms cannot be distinguished with clinical confidence from early SARS-CoV-2 infection.
- Our study highlights the critical importance of testing symptomatic individuals, even if they have recently been vaccinated, to ensure early detection of SARS-CoV-2 infection and help prevent future waves of COVID-19.
