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ARTICLE
COVID-19 After Vaccination in Lung Transplant Recipients: Real-Life Data

Objectives: The effectiveness of COVID-19 vaccines in lung transplant recipients is unclear. We retrospectively analyzed lung transplant recipients vaccinated with an inactivated virus vaccine (CoronaVac) and the mRNA vaccine BNT162b2 used against the SARS-CoV-2 virus in Turkey and shared their effects on COVID-19.
Materials and Methods: Demographic data of lung transplant recipients followed up for >3 months were collected, and vaccination dates and status against the SARS-CoV-2 virus were recorded. Recipients who received at least 3 doses of CoronaVac or 2 doses of BNT162b2, or 1 dose of CoronaVac plus 2 doses of BNT162b2, or 2 doses of CoronaVac plus 1 dose of BNT162b2 were considered fully vaccinated; those who were vaccinated less than this number were considered partially vaccinated. Patients with positive SARS-CoV-2 reverse transcription-polymerase chain reaction tests from respiratory tract samples were accepted as positive for COVID-19. Recipients were classified by number and type of vaccine, and groups were compared for infection, need for intensive care, and death as a result of COVID-19.
Results: Of the 53 lung transplant recipients, 51 were vaccinated (7 partially vaccinated, 44 fully vaccinated) and 2 were not vaccinated. Of fully vaccinated recipients, 13/44 received the inactivated vaccine, 5/44 received the mRNA vaccine, and 26/44 had a combination of the 2 vaccines. During the follow-up period, 13 patients (2/2 not vaccinated, 2/7 [28.5%] partially vaccinated, 9/44 [20.5%] fully vaccinated) were diagnosed with COVID-19. There was no significant difference in protection against infection between the inactivated, the mRNA, and combined vaccine groups. There was no significant association in cycle threshold values that determine the infection load and COVID-19 severity between transplant recipients who died and those who did not.
Conclusions: In lung transplant recipients, 3 doses of inactivated vaccine, 2 doses of mRNA vaccine, or the combined heterologous vaccine provided similar protection. Prevention of exposure is one of the most crucial steps.


Key words : Partial vaccination, SARS-CoV-2, Solid organ transplant

Introduction

The second year of the COVID-19 pandemic caused by the novel coronavirus has passed, but the world still has not fully returned to the prepandemic period. The pandemic caused restrictions and slowdowns in solid organ transplant (SOT) programs, as in every stage of life.1 The social life restrictions have begun to disappear thanks to vaccines developed against SARS-CoV-2. However, new variant epidemics have reimposed rules on social life restrictions. Vaccine studies aimed to reduce COVID-19-related health and social problems have resulted in different types of vaccines approved by the US Food and Drug Administration and European Medicines Agency.2 However, the effects of the vaccines in immunosup-pressed patients, such as lung transplant recipients, remain unclear.3

The vaccination program in Turkey started in January-2021 with priority given to groups with high risk of infection. The vaccine administered at the first stage was the CoronaVac (Sinovac Life Sciences, Beijing, China), an inactivated SARS-CoV-2 vaccine, approved for emergency use by the World Health Organization. In the first stage, those working in health institutions and living and working in places such as nursing homes for older adults, and then individuals over the age of 65 years, were vaccinated.4 Vaccination was then gradually expanded to all individuals over the age of 18 years. Lung transplant recipients started to be vaccinated after the prioritization of health care workers, nursing home residents and employees, and individuals over 65 years. Later, the mRNA vaccine BNT162b2 (Pfizer-BioNTech) was introduced. These 2 vaccines are currently in use in Turkey.

In this study, we examined lung transplant recipients who received a COVID-19 vaccine and analyzed the effects of vaccination with an inactivated and an mRNA vaccine on the course of the disease in lung transplant recipients.

Materials and Methods

This cross-sectional, retrospective observational study was initiated after approval was obtained from lung transplant recipients who were followed up at the Ankara City Hospital Lung Transplant Center (Ankara, Turkey) from March through December 2021. Recipients who had a lung transplant within the last 3 months and those with a prior history of COVID-19 before the vaccination program were excluded from the study, considering that they may affect the study results. Demographic data such as age, sex, transplant date, transplant indication, and comorbidities, as well as status and dates of vaccination against the SARS-CoV-2 virus, were recorded. Based on the data of the Ministry of Health, the approximate daily cases for each month was calculated and its correlation with our cases was investigated.5

In Turkey, the Ministry of Health accepts and recommends 2 doses of the mRNA vaccine or at least 3 doses of vaccination, including the inactivated vaccine, as a protective measure for all individuals. After December 2021, booster dose administration came to the fore to protect against the newly emerging variant viruses. At the beginning of the vaccination period, our lung transplant recipients were vaccinated with the inactivated vaccine (CoronaVac), the first vaccine provided for their age. In the following booster doses, the vaccine preferences increased to 2 options with the later procured mRNA vaccine. Inactivated and mRNA vaccine studies were explained in light of the current literature to our lung transplant recipients, and the patients were asked to choose the vaccine option. Although some of our patients preferred to continue with inactivated vaccines, some preferred the mRNA vaccine.

In line with the recommendations of the Turkish Ministry of Health,6 those who received at least (1) 3 doses of CoronaVac or 2 doses of BNT162b2 or (2) 2 dose of CoronaVac plus 2 doses of BNT162b2 or (3) 2 doses of CoronaVac plus 1 dose of BNT162b2 were considered fully vaccinated (FV), and those vaccinated less than this number were considered partially vaccinated (PV).

Patients who showed clinical signs and symptoms suggestive of respiratory tract infection and were found positive in the SARS-CoV-2 reverse transcription-polymerase chain reaction test from respiratory tract samples were considered COVID-19 positive. Viral load was estimated by obtaining the cycle threshold values (Rotor gene 5ple, QIAGEN). Those who needed high-flow oxygen therapy due to lung involvement or intensive care due to the need for intubation were classified as the high severity patient group, whereas those who did not need oxygen, needed nasal oxygen, or had adequate oxygenation with a reservoir mask (oxygen saturation pressure >92%) were classified as the mild-moderate severity patient group.

The time since the last vaccination was determined by the day of infection diagnosis for recipients diagnosed with COVID-19 and by the termination day of the study (December 31, 2021) for COVID-19-negative recipients. Recipients were classified by the number and type of the vaccine, and groups were compared for infection, need for intensive care, and death as a result of COVID-19.

Statistical analyses
Data were encoded and recorded using IBM SPSS for Windows version 22.0 software. Descriptive statistical methods (mean, standard deviation, median, frequency, and ratio), Shapiro Wilks test, and box plot graphics were used to evaluate the conformity of the variables to the normal distribution. The Mann-Whitney U test was used for the intergroup comparisons of nonnormally distributed parameters. The chi-square test was used for independent group comparisons for categorical variables. The results were evaluated with 95% CI and a significance level of P < .05.

Results

Of the 63 lung transplant recipients, 53 patients were included in the study. Two recipients were not vaccinated because of their extreme doubts about the side effects of the vaccines. The other 51 received at least 1 dose of the inactivated or the mRNA vaccine. Seven patients were considered as PV, and 44 were considered as FV (Figure 1).

After the vaccination program, 13 patients were diagnosed as COVID-19 positive (2 not vaccinated, 2 PV, and 9 FV; Table 1). The median age of COVID-19-postive patients was 56 years (range, 30-64 years), and the mean time of diagnosis posttransplant was 44 months (range, 15-96 months). Four patients were treated in the intensive care unit. Mild symptoms were observed in 2 recipients who were not vaccinated, whereas 3 FV recipients died as a result of breakthrough SARS-CoV-2 infection.

Eleven of 51 recipients who received at least 1 dose of vaccine (21.6%; 2 PV and 9 FV) were infected with SARS-CoV-2. The rate of infection in lung transplant recipients paralleled the national rate (Figure 2).5 The reduction of social life restrictions and the withdrawal of some of them, the emergence and rapid spread of new variants, the confidence of being vaccinated, and the insensitivity of people to protective rules may have affected the national case numbers.

The infection rate was 28.6% (2/7) in PV recipients and 20.5% (9/44) in FV recipients (P = .628). Table 2 presents vaccination status, vaccine types, median age, and median postvaccination time in each vaccine group. There was no significant difference within the FV vaccine groups in terms of protection against infection (P > .05). There was also no difference in protection against infection between the 3 doses of inactivated vaccine and the other FV group (2/13 [15.3%] vs 6/31 [19.4%], respectively; P = .780). When we compared those who received 2 doses of the mRNA vaccine (2 BNT162b2, or 1 CoronaVac + 2 BNT162b2, or 2 CoronaVac + 2 BNT162b2), which is considered protective in Europe and the United States (recommendations before the Omicron variant period), with other FV recipients (3 CoronaVac or 2 CoronaVac + 1 BNT162b2), we observed no difference in terms of protection from infection (2/11 [18.2%] and 7/33 [21.2%], respectively; P = .870).

When we compared lung transplant recipients who were COVID-19 positive versus COVID-19 negative, the follow-up time after the last vaccination of those who had at least 1 dose of vaccine was significantly different (49 days [range, 25-149] vs 147 days [range, 70-305], respectively; P < .001). A comparison of the follow-up time after the last vaccination between recipients who were COVID-19 positive versus COVID-19 negative in the FV group also revealed a significant difference (49 days [range, 35-127] vs 148 days [97-206], respectively; P < .001).

Of the 11 breakthrough infections in lung transplant recipients, 2 recipients (18.2%) were in the PV group and 9 (81.8%) were in the FV group (Table 3). A further analysis showed that 4 recipients (36.3%) were in the high severity group and required intensive care follow-up, and 3 recipients (27.2%) died. The median time since the last vaccination was 49 days (range, 25-149 days), with median time since last vaccination for deceased lung transplant recipients versus those who did not die of 42 days (range, 37-49) versus 99 days (range, 25-149), respectively. There was no statistically significant difference between the median time after the last vaccination in living versus deceased recipients (P = .279).

No recipients had an infection in the early period after vaccination (<14 days). There was no difference between the median ages of patients requiring and not requiring intensive care admission (61 years [range, 44-61] vs 58 years [range, 33-66]; P = 1.0). Although the median age of the deceased patients (61.0 years) was higher than patients who did not die (54.0 years), the difference was not statistically significant (P = .630). The median polymerase chain reaction cycle threshold at the time of infection was 25.35, and there was no significant difference between patients who died and those who did not (median value of 26.08 [range, 23.45-29.06] and 23.84 [range, 19.02-28.55], respectively; P = .271).

Discussion

The course and effects of COVID-19 in SOT recipients remain unclear.7,8 With the newly introduced COVID-19 vaccines, studies have begun on the extent to which vaccines are protective in SOT recipients.9 However, such studies are extremely scarce for lung transplant recipients. In particular, studies investigating the effects of the inactivated vaccine in lung transplant recipients are only case reports.10 With newly emerging variants, studies have reported that 2 vaccine doses did not elicit an adequate immune response in immunosuppressed patients, such as SOT recipients, and breakthrough infections began to appear.11,12 However, among these publications, breakthrough infections reported among SOT recipients after inactivated vaccine and heterologous vaccine (inactivated vaccine followed by mRNA vaccine), applied in our country of Turkey, are not available in the current literature.

Previous studies stated that vaccines protected against infection and severe disease and emphasized that those who died were older adults with high comorbidities.13-18 In addition, compared with other vaccines, neutralizing antibody levels were significantly lower after the inactivated vaccine in SOT recipients over 60 years of age.19 The higher median age of our patient group who died (61.0 years) versus those who did not (54.0 years), although not statistically significant, may have clinical significance. On the other hand, contrary to investigations that reported that antibody levels decreased in direct proportion to the time elapsed after vaccination, and thus the vaccine protection decreased, the time from the last vaccination to the infection of the patients who died in our study was shorter.20

Several studies have reported that the protective effects of COVID-19 vaccines are correlated with neutralizing antibody titer levels and that the neutralizing antibody titer levels in those vaccinated with the inactivated vaccine are significantly lower than levels shown with the mRNA vaccine.21,22 In addition, recent studies have determined that the antibody concentration drops significantly 6 months after 2 doses of the inactivated vaccine and increases after the third dose of the inactivated vaccine, but if the third dose is the mRNA vaccine, the antibody level increases much more than the group vaccinated with the inactivated vaccine.23,24 We did not check antibody levels in our study. However, there were no significant differences in our real-life data in terms of infection rate between the groups who received inactivated vaccine, mRNA vaccine, or booster-dose mRNA vaccine following the inactivated vaccine in terms of protection from both infection and death.

The main expectation of health care professionals with regard to vaccinations is to reduce the infection rate and the related morbidity and mortality. Breakthrough infection rates reported in retrospective studies of SOT recipients who received 2 doses of the mRNA vaccine were less than 5% with a mortality rate of 0% to 15%; however, the cross-sectional study periods were only from 1 to 12 months.25-27 In our study, the rate of breakthrough infection in the FV group was 20.5%, and death after breakthrough infection was observed in 3 of 11 patients (27.7%). It may not be correct to attribute the difference in breakthrough infection rates between our study and other studies to the heterogeneity of our vaccine groups. It is evident that breakthrough infections during the pandemic are affected by the vaccine scheme applied, the circulating variants, the prevalence of the infection in the community, and the continuity of the patient’s compliance with masks, social distancing, hygiene rules, vaccination, as well as adherence to social life restrictions (quarantine) and the vaccination rate of the general population. The large family structure, owing to the social and cultural characteristics of our lung transplant recipients in Turkey, the vaccination status of the family members, and their high risk of transmission due to school and work may have caused the rate of breakthrough infections to be higher in our study patients.

The cross-sectional interval that overlapped with the epidemic peaks in other studies and the duration of the cross-section interval may also have affected the infection rates. Indeed, in our study, which was over a 10-month period, the number of recipients with infection returned to zero during the period of restrictions and increased during the period when restrictions were reduced or removed (Figure 2). In addition, it may not be correct to report the mortality rate, because our sample contained a small number of cases.

It has been suggested that protection decreases with the time elapsed after vaccination.20 Recent studies have reported that the median days from the second dose of vaccination to COVID-19 diagnosis can range from 30 to 90 days.26,28 In our study, breakthrough infections were observed in the first 2 months after vaccination (median of 49 days) and the time since vaccination (median of 147 days) in COVID-19-negative recipients was significantly longer. This may also indicate that the recipients felt safer in the early postvaccination period and eased protective protocols.

The polymerase chain reaction cycle threshold value determines the viral load. As the viral load increases, cycle threshold values decrease. Although the cycle threshold value was expected to be lower in patients with more severe disease, it was interestingly higher in our deceased patient group, although not statistically significant, which is consistent with the findings of Deng and associates.3 In the report published jointly by the Infectious Diseases Society of America and the Association for Molecular Pathology, it has been stated that many factors affect the cycle threshold value, including patient-related factors, sample collection and storage conditions, and test characteristics. Hence, the relationship between this test and the severity of the disease should be interpreted correctly.29

The most important limitations of our study are its single-centered, retrospective, and observational design, the heterogeneous and low number of cases in the vaccinated groups, the absence of coronavirus sequence analysis, and the lack of protective antibody level results after vaccination and at the time of infection. However, our study is important because it presents real-life data of lung transplant recipients who received vaccinations with the mRNA, the inactivated, or heterologous (inactivated + booster mRNA) vaccines and, to our knowledge, is the only such study in the literature in lung transplant recipients.

Conclusions

Our results showed that COVID-19 vaccination in lung transplant recipients with the inactivated vaccine alone or with the inactivated vaccine and the booster dose mRNA vaccine resulted in similar breakthrough infection events versus mRNA vaccine alone. However, these may change with possible future variants. In addition to vaccination, mask and social isolation rules for protection are still valid as the most straightforward method that can be applied, especially in SOT recipients who do not produce an adequate immune response.


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DOI : 10.6002/ect.2022.0088


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From the 1Department of Thoracic Surgery and Lung Transplantation Clinic, the 2Department of Anesthesiology and Reanimation, and the 3Department of Infectious Disease, University of Health Sciences, Ankara City Hospital, Ankara, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Sinan Turkkan, University of Health Sciences, Ankara City Hospital, Thoracic Surgery and Lung Transplantation Clinic, Üniversiteler Mahallesi 1604. Cadde No: 9 Çankaya/Ankara, Turkey
Phone: +90 505 3575829
E-mail: dr.turkkan@hotmail.com