The overall relative risk (RR) of infection in recipients of two doses compared to the unvaccinated population was 0.93 (95% CI: 0.880.99), while the overall VE was 7%. By age group, the relative risk was statistically significant for people over 75 (0.45; 95% CI: 0,34-061), corresponding to a VE of 55% (Table 7). There was no statistical significance for other age groups. Those vaccinated with three doses had an RR vs. the unvaccinated of 0.65 (95% CI: 0.61-0.69), with a VE of 35%. Analysed according to age group, the relative risk decreased from 0.71 in the 18-49 group, through 0.69 in the 50-64 group, to 0.46 in people above 75, corresponding to the VE of 29%, 31% and 54%, respectively. Comparing people vaccinated with three doses with those who received two doses, RR was 0.69 (95% CI: 0.64-0.75), with a VE of 31%. A statistically significant difference in the risk of disease was found in the age groups 18-49 (RR 0.72; 95% CI: 065-0.79; VE 28%) and 50-64 (RR 0.76; 95% CI: 0.64-091; VE 24%). Table 8 shows RR and VE by age and vaccine type for the population vaccinated with three doses compared to those who did not receive the third dose. The highest overall effectiveness was achieved by the BNT162b2 vaccine (42%; 95% CI: 38-45%) and the lowest with BBIBP-CorV (27%; 95% CI: 23-32%), while the VE of Gam-COVID-Vac was in the middle (40%; 95% CI: 36-44%). The AstraZeneca ChAdOx1 vaccine could not be statistically evaluated in this context due to the small number of persons who received three doses of this vaccine. Importantly, the VE of all vaccines depended on the age group observed. For instance, although the overall effectiveness of BBIBP-CorV was 27%, it was only 18% effective in the age group 50-64, but as much as 49% in people over 75. The effectiveness of BNT162b2 was not significant in persons aged 65-74, while in the other age groups it varied between 40% and 64%, increasing with the age of the vaccines. The vector vaccine Gam-COVIDVac yielded a similar a pattern, from its minimal VE of 28% in the youngest population (18-49) to the maximal VE of 64% in people over 75.

Table 7: COVID-19 vaccine effectiveness in different age groups by number of doses.

Table 8: Vaccine effectiveness (by type of vaccine) in different age groups in people who received three COVID-19 vaccine doses as compared to those who did not receive the third dose.

Discussion

Vaccine development has endowed humankind with an invaluable tool to protect lives and wellbeing in the recent COVID-19 pandemic. Vaccines have successfully reduced the rates of symptomatic infection, hospitalization and mortality in various populations and clinical settings [15,16]. However, measured VE displayed considerable variation, particularly after the onslaught of novel SARS-CoV-2 variants, and investigations of VE in different real-life circumstances could be crucial for appropriate vaccination policy against this still evolving virus, as well as for the timely response to future pandemics, including those potentially brought about by as yet unknown pathogens (“disease X”) [17,18]. The Belgrade municipality of Voždovac may be considered a reasonable testbed for investigating VE, given that its demographic structure is roughly representative of urban communities in Serbia and that overall COVID-19 vaccination coverage in this municipality (52.4%) was very close to the national average. For the investigated period, we found a very modest VE against symptomatic infection (in aggregate, 7% for two doses and 35% for three doses), much below the value typically found in real-world studies [19]. However, at least six months had elapsed since the second dose, and the limited VE is likely to be due to the expected waning of the humoral immune response against SARS-CoV-2 with time [20-22], since neutralizing anti-SARSCoV-2 antibodies prevent virus from entering into host cells [23] and thus alone may block the infection prior to appearance of any symptoms. Unfortunately, we were not able to obtain data on VE against hospitalization and death for the same time period in the same population. The latter would arguably be more appropriate outcome measures, considering a somewhat greater durability of the cellular immune response compared to the humoral [24]. The latter takes more time to mobilize, exerts its protective effects only after the virus has entered host cells, and is therefore thought to affect general disease outcome much more than the likelihood of appearance of symptoms per se.

The measured VE in our observed population increased with age. Indeed, after receiving only two vaccine doses, it turned out to be significant only in people over 75 (55%). After three doses, VE was 29% in the group aged 18-49, 31% in the 50-64 group, insignificant in the 65-74 group, and 54% in those over 75, virtually coinciding with VE after two doses for this age group. This evidence of a considerable protective effect in the elderly, even after six months, arguably represents the most significant finding of our study, given that people of advanced age have been shown early in the pandemic to be particularly vulnerable to harmful consequences of COVID-19 [25] and subsequently confirmed to benefit extensively from vaccination [26]. It is therefore encouraging to find that the protection in this population appears to have held even after it had waned in other age groups. However, differential exposure of the elderly population to SARS-CoV-2 may have also played a role in this result, since it is plausible to assume that elderly citizens who accepted the recommendation to get vaccinated exhibited less pandemic-related paranoid ideation and therefore also largely accepted to wear protective masks, limit interpersonal contacts and avoid mass gatherings [27].

The VE measured after three vaccine doses also exhibited marked differences according to the type of vaccine, ranging from 27% for BBIBP-CorV to 40% for Gam-COVID-Vac and 42% for BNT162b2 (VE for ChAdOx1 could not be evaluated due to insufficient subsample size). While this direct comparison of effectiveness of vaccines built upon three different platforms (conventional inactivated, RNA-, and vector-based) may also be considered an important strength of our study, relating its results to those obtained in other real-world studies remains a challenge due to a number of factors [28]. Foremost among the latter are constant shifting of predominant viral variants, possible variation in spatiotemporal distrubution of risk factors in respective populations, and a dynamic relationship between ongoing viral evolution and the state of collective immunity. Still, our results are consistent with those of a number of studies attesting to a superior VE of RNA- and/or vector- based vaccines over vaccines with a conventional inactivated virus design, including those from Hong Kong [29], Buenos Aires [30] and Colombia [31], as well as an extensive meta-analysis of a plethora of other studies [32]. Our results are also, in a way, complementary to literature data attesting that all vaccines against COVID-19 showed considerable effectiveness against symptomatic infection up to six months after the second dose [33].

In this light, VE we found after three vaccine doses primarily reflects the well-documented boosting effect [34], coupled with the fact that humoral immune response had not yet had the time to massively wane following the third dose [21]. By the same token, relatively poor protection after two doses can be explained by the combination of waning of immunity with time and the predominance of the then novel Delta variant of SARS-CoV-2 at the time of study, partially bypassing the immune memory elicited by earlier infection or vaccination [35], a phenomenon later found to be even more pronounced after the emergence of the Omicron variant [36]. Since both processes appear to affect humoral immunity more than cellular, one could expect a more solid protection against severe or life-threatening consequences of SARS-CoV-2 infection [37-39] – something that we, again, were unfortunately unable to assess in this study. However, in nearby Hungary, Vokó and collaborators, whose results regarding symptomatic infection are very similar to ours, indeed found more solid and durable protection against lethal outcome of COVID-19 [40].

The downward temporal trend in VE against symptomatic infection can be easily traced by comparing our results with those of studies pertaining to earlier time periods in the course of the global vaccination campaign: the study of Petrović et al. [5], covering the initial four months, and that by Kokić, Kon and Djurković-Djaković [4], conducted from six to eleven months after the onset of COVID-19 vaccination. In this light, our data may be considered a natural extension of data gathered in the latter two studies, offering further insight into the dynamics of post-vaccinal immunity to SARS-CoV-2. In summary, we appear to have found both evidence of limited duration of immunity acquired by vaccination against COVID-19 against symptomatic infection and an attestment that, at least in the most vulnerable age group, a significant level of protection may still linger beyond six months after the primary vaccine series.

Conclusion

The results of this study demonstrate a significant overall effectiveness of vaccination against symptomatic COVID-19 infection in people over 75 years of age six months or more after the second dose, as well as a significant protection in most age groups up to five months after the third dose. Vaccination effectiveness also varied considerably by type of vaccine and was the highest for BNT162b2, closely followed by Gam-COVID-Vac. However, further research is needed to better understand the longterm effectiveness of different vaccine types, as well as to assess potential variations in protection across different populations and emerging variants.

Ethics Statement and Conflict of Interest

This study was approved by the Institutional Review Board of the Community Health Center Voždovac. The authors declare no conflict of interest.

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