Reinfection rates, change in antibody titers and adverse events after … – BMC Infectious Diseases

We found that study participants who received mRNA vaccines as primary series had the lowest reinfection rate and the highest increase in antibody titers. Those who received inactivated virus vaccines had the highest reinfection rate and the lowest rise in antibody titers. In terms of individual brands of COVID-19 vaccine, there were no identified cases of probable reinfection among participants given inactivated Vero Cells and Ad26.COV2.S vaccines as primary series. However, these two brands had the lowest number of recipients (only one and nine participants received the inactivated Vero cells vaccine and Ad26.COV2.S vaccines, respectively). We observed the highest reinfection rate among vaccinees who received Sputnik V, followed by CoronaVac.

We noted that the highest reinfection rate was observed among participants who received Sputnik V (Gamaleya) despite the large rise in antibody titer after primary series vaccination. This may be due to other variables that influence reinfection rates, including age, co-morbidities, employment, and exposure to COVID-19 [10].

The reinfection rates of the unvaccinated and partially vaccinated study participants were paradoxically lower compared to those who were fully vaccinated, regardless of type of vaccine. This may be explained by the epidemiologic context in relation to the timing of vaccination, as shown in Fig.2. There were two COVID-19 surges in the Philippines during the study periodthe Delta variant surge in August-October 2021 and the Omicron variant surge in January-February 2022. Of the 64 cases of probable reinfection, 6 (9.4%) occurred during the Delta variant surge while 39 (60.9%) occurred during the Omicron variant surge. During the time of these surges, majority of study participants were already fully vaccinated. Thus, the lower reinfection rates of the unvaccinated and partially vaccinated study participants may reflect the lower incidence of COVID-19 infection in the Philippines during the start of the study period.

Epidemiological context in the Philippines and the vaccination status of study participants. (Image modified from the https://doh.gov.ph/covid19tracker) [11]. BE1=first blood extraction at day 21, BE2=second blood extraction at day 90, BE3=third blood extraction at day 180, BE4=fourth blood extraction at day 270, BE5=fifth blood extraction at day 360,

Our findings are consistent with other studies that found that higher antibody levels were associated with a lower risk of COVID-19 infection [12]. In our study, those who received mRNA vaccines primary series had the largest rise in antibody titers and correspondingly, the lowest reinfection rate. These findings are also consistent with the results of systematic reviews showing that vaccine effectiveness against COVID-19 infection was highest for the primary series of mRNA vaccine [4, 5].

The mRNA vaccines consist of a lipid nanoparticle enveloping an mRNA molecule that encodes the viral Spike protein. This vaccine induces antigen-specific follicular helper T cell development in the germinal centers of the draining lymph nodes, which would lead to B cell activation, antibody isotype switching, affinity maturation, and formation of plasma cells and memory B cells [13]. This mechanism of action closely resembles the immune response to a natural infection, which may explain why mRNA vaccines stimulate higher antibody titers and consequently, produce greater effectiveness against COVID-19 infection, hospitalization, and death [14].

We also observed that the GMT ratio of all types of vaccine exceeded 4. A four-fold increase in antibody titers is generally the minimum rise interpreted as an adequate antibody response [15]. This supports the findings of studies in other countries that the various types of vaccines demonstrate acceptable immunogenicity despite variation in the actual magnitude of humoral response [16]. Among the seven brands of COVID-19 vaccines received by the study participants, only the inactivated Vero cells vaccine had a GMT ratio less than 4. However, only 1 participant received this vaccine.

Among the study participants who received booster doses, the largest GMT ratios were observed among those with inactivated virus vaccine as the primary series, likely due to the lower pre-booster titer compared to those who received viral vectors and mRNA vaccines as primary series. An inverse relationship with pre-immunization titer level and degree of humoral response has been demonstrated in other studies, where a higher pre-vaccination titer is associated with a lower rise in antibody post-vaccination [17].

The GMT ratio was higher with heterologous boosters after inactivated virus and viral vectors primary series compared to homologous boosters. However, among those who received mRNA vaccine as primary series, the GMT ratio was higher for those given homologous boosters compared to heterologous boosters. These findings are consistent with studies in other countries reporting better immunogenicity for heterologous compared to homologous boosters for inactivated virus vaccines, and conversely, better immunogenicity for homologous boosters for mRNA vaccines [18, 19]. The lower GMT ratio of heterologous booster for mRNA vaccine may be due to the use of viral vectors as the booster in 5 out of the 20 participants. As shown in our study and in other published studies, viral vector vaccines generally result in a smaller rise in antibody titers compared to mRNA vaccines. Our findings suggest that the administration of mRNA vaccines as booster, whether as a heterologous booster or homologous booster, results in larger rise in antibody titers.

In this study, adverse events following immunization were more frequently reported among mRNA and viral vector vaccines compared to inactivated virus vaccines. This finding is consistent with other studies [6, 20]. Increased vaccine reactogenicity has been associated with higher post-vaccination antibody levels [21]. This was observed in this study, with participants who received inactivated virus vaccines having the lowest GMT ratio and also the lowest percentage of adverse events following immunization.

Our study had the following limitations. First, in the primary cohort study we conducted, we could not do laboratory confirmation of reinfection due to the unavailability of routine genomic testing for symptomatic patients. Instead, an adjudication committee determined whether reported events were probable reinfections. Hence, the reinfection rates we report in this study refer to probable reinfection rather than confirmed reinfection. Furthermore, reinfection rates in the main cohort study were probably underestimated because testing via RT-PCR or antigen test was encouraged but not provided for free for participants with symptoms consistent with COVID-19. Some symptomatic study participants refused to undergo testing. The study was also unable to detect cases of asymptomatic reinfection. Thus, the reinfection rates reported in this study are likely to be underestimated.

Another limitation is that the antibody titers measured were binding antibodies, not neutralizing antibodies. Tests for neutralizing antibodies are ideal since these are the antibodies that directly interfere the binding and uptake of virus to the host cells [21]. At the time the cohort study was being conducted, there were no certified biosafety level 3 laboratories in the country. However, studies have demonstrated neutralizing antibodies strongly correlate with RBD-specific binding antibodies, and that RBD-specific binding antibody titers can serve as surrogate measures for neutralizing titers [22].

Another limitation in this study is the variation in the timing of antibody titer determination in relation to vaccination, since antibody tests were performed at fixed time points based on the initial COVID-19 infection. Means and standard deviations of the number of interval days between the antibody determination and vaccination were reported to provide appropriate context to the results.

Moreover, the semi-quantitative laboratory test used in the study had an upper limit of detection of 250 U/mL. We performed 10-fold dilution according to manufacturer recommendations to increase the upper limit of detection to 2,500 U/mL. However, several results still exceeded 2,500 U/mL. We performed 100-fold and 1,000-fold dilutions to increase the upper limit of detection to 250,000 U/mL; however, the resulting values at this higher range may have diminished accuracy.

Another limitation is the presence of several confounding variables that affect reinfection rate and antibody titers aside from vaccination. Due to these issues, and the small sample size of the completed cohort study, this study was designed as a descriptive study and the results are intended to be exploratory in nature. Inferential statistics was not done.

Furthermore, the completed cohort study primarily aimed to determine symptoms of COVID-19 reinfection during the follow-up calls. Participants were also asked if they received the COVID-19 vaccine, and the type, brand and date of vaccination. From this recorded data, adverse events following immunization were extracted. However, this is prone to reporting bias. Although COVID-19 symptoms have several similarities as systemic adverse events following immunization, other symptoms such as rashes, flushing or local erythema which were not directly asked by the researchers may have been missed if the information was not volunteered by the study participants. Moreover, data for this study was heavily reliant on the completeness and accuracy of the data recorded in the completed cohort study.

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Reinfection rates, change in antibody titers and adverse events after ... - BMC Infectious Diseases