Compared to findings in controlled settings, modest reduction has been observed in vaccine effectiveness in real world situations, with protection rates against COVID-19 varying from 24-65%.1,2 The percentage of vaccinees developing symptomatic COVID-19 was low (<1%) in randomized controlled trials of ChAdOx1 nCoV-19. In the real-world settings, however, high SARS-CoV-2 infection and disease rates have been observed in vaccinated individuals. In our previously published study, lab confirmed COVID-19 was seen in 41% individuals who received only one dose and around 20% individuals receiving both doses of the vaccine. Corresponding rates were around 67% and 35% in subgroup of ‘doctors’ recruited in the study. Most of the infections in our study were observed to be breakthrough and were mild in severity.3 Here we have analysed the spectrum of symptoms in COVID-19 in vaccinated individuals, the risk factors of breakthrough infections, and the risk factors of moderate to severe disease in vaccinated individuals.
The commonly occurring symptoms in vaccinated individuals in this study were fever (72%), followed by features of rhinitis (41%) and cough (34%). Around 5% of individuals with lab confirmed COVID-19 were completely asymptomatic and around 7% had only one symptom. Cardiovascular involvement in the form of significant changes in blood pressure was observed in 2.4% and majority of these patients reported an elevation of blood pressure during the illness. Atypical organ involvement in the form of ocular symptoms was observed in more than 2% of affected, emphasizing the need to be vigilant against atypical symptoms and signs in the face of changing variants of SARS-CoV-2. Around 11% had some post COVID-19 complaint at two months follow up, most common being generalized weakness. This attains special significance in future deliberations of how vaccines may have any role of importance in long COVID. Post-vaccination COVID-19 symptomatology has not been elaborated widely. In a metanalysis conducted in the pre-vaccination period, prevalence of COVID-19 in health care workers has varied from 0.4 to 57% with females constituting the majority. Fever, anosmia, and myalgia were the commonest symptoms.5
In the current study, on logistic regression analysis, occurrence of COVID-19 was statistically more common in females (OR 1.6), in the younger age group (OR 1.6), in individuals who were overweight (OR 1.4) and in those who received only one dose of the vaccine (OR 2.9). The risk association of COVID-19 with age, gender and BMI was corroborated when regression analysis was performed on individuals receiving two doses of the vaccine. High BMI, previously, has been associated with severe form of COVID-19.6,7 While males and females are believed to have a similar susceptibility to the acquisition of the disease, some studies have shown a higher incidence rate of COVID-19 in females, particularly among health care workers.8 Geographical variations also exist with respect to gender and susceptibility to COVID-19. In certain regions of Peru for example, the incidence rate of COVID-19 was shown to be higher in females than males.9 Interestingly, females are also at higher risk of getting adverse events following immunization with COVID-19 vaccines.4,10,11 No difference in the occurrence of COVID-19 was seen with respect to other variables such as pre-vaccination history of COVID-19, medical co-morbidities and with the use of RAAS blockers. Since the emergence of COVID-19, the members of RAAS blocker class were hypothesized to enhance the propensity towards SARS-CoV-2 infection as well as severe COVID-19 disease. However, the association of these drugs with disease severity was refuted in some of the largest meta-analyses conducted by us and others.12,13 The absence of a relation between COVID-19 occurrence in vaccinated people and pre-vaccination history of prior infection may imply that boosting effect of vaccines on naturally acquired immunity needs to be explored further.
Dosing interval was observed to be a significant influencer of occurrence of COVID-19 in this study. More than six times (OR 6.7) and nearly 1.6 times higher risk of contracting the disease was observed in individuals receiving two doses of vaccine at ≤ 30 days interval compared to those who received the second dose at gap of more than 60 days and at 31-60 days, respectively. The corresponding risk was more than four times (OR 4.13) in those receiving second dose of vaccine at 31-60 days compared to those who got the second dose at an interval exceeding 60 days with marginal statistical significance (P 0.059). Overall, better protection rates have been demonstrated with increase in the dosing interval of ChAdOx1 nCoV-19 vaccine. This was one of the reasons provided by various drug regulatory authorities, for increasing the dosing interval of ChAdOx1 nCoV-19 from 28 days to 84 days.14
With respect to severity of COVID-19, statistically significant association was seen with gender, pre-existing lung disease, use of RAAS blockers and number of doses of vaccine. Except the use of RAAS blockers, the association of remaining three factors remained statistically significant on logistic regression analysis too. Males and those receiving only one dose of the vaccine had close to 3 times higher odds of developing moderate-severe form of the disease compared to females and those receiving both doses. With marginal statistical significance (p=0.08), individuals with pre-existing lung disease were at more than three times risk of developing moderate to severe COVID-19 compared to those with no pre-existing lung illness. The risk association of severity of COVID-19 was enhanced in the regression analysis confined to individuals receiving two doses of vaccine (n=382) with an odds ratio for male gender of 3.6 and OR of 5.9 for pre-existing lung disease. Males have been found to be at higher risk of severe form of COVID-19 in several other studies done in the pre-vaccination period.6,7 Increased COVID-19 severity in males might be explained to some extent by androgen facilitated SARS-CoV-2 entry or immune regulation by male hormones. Testosterone can positively up regulate the expression of ACE-2 and possibly of TMPRSS2, both of which are involved in SARS-CoV-2 S protein entry and infectivity.15 Testosterone is also known to blunt the protective functions of neutrophils, macrophages, and dendritic cells against the invading pathogen.16 Asthma was the predominant pre-existing lung disease in our vaccinated cohort. Evidence surrounding association of asthma with COVID-19 morbidity and mortality is conflicting. While CDC suggests moderate-severe asthma to be a potential risk factor of severe form of COVID-19, no significant association was claimed between asthma and disease severity by others.17 Severity of COVID-19 may also be governed by the Th phenotype of asthma as has been suggested by some.17,18
Though a numerically higher percentage of individuals above 40 years of age, overweight individuals, those with past history of COVID-19 and those with co-morbidities was seen in the group developing the severe forms of disease, the association of these factors was not statistically significant with disease severity. Old age, obesity, diabetes mellitus, hypertension, kidney disease and immunosuppression are some of the predictors of worse COVID-19 outcomes in earlier studies.19 Absence of association of COVID-19 severity with these factors in our study should be taken with caution as the population chosen was predominantly composed of the young and percentage of those with co-morbidities was low. The findings, hence, may not be extrapolated to the general population. Dosing interval was not a statistically significant predictor of severity of disease.