Immunity After Vaccination Against SARS-CoV-2 in Lung Transplant?

BACKGROUND: SARS-CoV2 infection causes high morbidity and mortality in lung transplant (LT) recipients. Vaccination with messenger RNA vaccines has been shown to play a key role in controlling the severity of infection in the general population. The aim of our study is to analyze whether vaccination with 2 doses of SARS-Cov2 provides immunity in LT recipients.
METHODS: Retrospective descriptive and analytical study of LT recipients vaccinated with 2 doses of SARS-CoV2. We analyzed the vaccine received, if they had COVID-19, antibody levels (antispike and antinucleoprotein), anticalcineurin levels, infections in the last year, and presence of neoplasias.
RESULTS: The most commonly administered vaccine was from Moderna, with 27% of patients showing immunity with a median antibody levels of 4.81 binding antibody units/mL, far from the values considered protective (> 34 binding antibody units/mL). Thirteen patients were infected with SARS-CoV2, 7 post vaccination (5 of them were antispike-positive). No relationship was demonstrated between generation of immunity and age and level of immunosuppression.
CONCLUSIONS: Vaccination against SARS-CoV2 in LT recipients generates limited and ineffective immunity with only 2 doses.

antibody binding units

coronavirus disease 2019

immunoglobulin G

milliliter

messenger ribonucleic acid

lung transplant

ribonucleic acid

spike

severe acute respiratory syndrome coronavirus 2

INTRODUCTION

Coronavirus disease 2019 (COVID-19) is the SARS CoV2 infection; described in 2019 in China (1). In immunosuppressed patients, the risk of developing COVID-19 is higher than in the general population(2), producing moderate-severe pneumonia in lung transplant patients (LT) and requiring hospitalization in most cases (88%). This is due to higher levels of immunosuppression in LT than in other solid organ transplant recipients, as well as the existence, in some of them, of impaired lung function and the fact that the target organ of COVID-19 is the lung (1,3). In addition, virus infections, such as SARS-CoV2, can also lead to chronic allograft dysfunction in these patients (4).

Vaccination plays an important role in slowing the spread of the virus and promoting the elimination of the virus from the host. The SARS CoV2 virus is made up of RNA containing proteins such as S (spike) which promotes binding between the host cell and the virus, and between the infected cell and adjacent uninfected cells; it is also the main inducer of neutralizing antibodies in vaccines (4).

In immunocompetent patients, mRNA-based vaccines (Moderna, Pfizer/BioNTech) have shown high efficacy (>90%) in preventing infection and, if it occurs, less severe infection (1,5). Clinical trials initially conducted with these vaccines did not include LT or other immunocompromised patients, so their efficacy in these patients was unknown, although it was suspected that the response was lower than in immunocompetent patients, as is the case with other vaccines. This lower immunogenicity is probably related to immunosuppressive treatment, which also has higher levels in lung transplantation compared to other solid organ transplant (5,6)..

Despite this, international societies recommend vaccination in LT, as well as in patients with advanced lung disease who are on the waiting list, as it provides protection against severe COVID-19. Furthermore, the prevalence of allograft dysfunction and other side effects are low (5).

In Europe, a study has been conducted in Prague, with a small simple of LT in which no immunity was found (5).

The aim of our study is to assess whether 2-dose vaccination against SARS-CoV2 provides immunity in LT and whether older age and/or a higher degree of immunosuppression influence the vaccine response.

MATERIAL AND METHODS

This is an observational, retrospective, descriptive and analytical study. The inclusion criteria were be LT at the Hospital Universitario 12 de Octubre in Madrid and to be vaccinated with 2 doses against SARS-CoV2, the last of them during the period between January 2021 to September 2021.Patients who received one dose and those who were not vaccinated were excluded.

As an immunosuppressive regimen, all patients received basiliximab induction and then maintenance triple therapy based on a calcineurin inhibitor, a purine synthesis inhibitor and steroids.

The variables collected were age, sex, underlying disease leading to transplantation, time from transplantation to analysis, type of transplantation, type of vaccine received, whether they had SARS-CoV2 infection and when it occurred (before or after vaccination and in this case how long after vaccination), number of infections in the last year, existence of neoplasia, levels of anticalcineurinic agents in the last pre-vaccine sample (sub-therapeutic, in adequate range or supra-therapeutic), levels of antibodies against SARS-CoV2 (anti-spike and anti-nucleoprotein measured by DiaSorin RiS IgG), taking the measurements 4 months post-vaccination and considering as positive levels greater than 34 antibody binding units/ml (AU/ml).

Statistical analysis of qualitative variables was performed using chi-square. A p value <0.05 was considered statistically significant. The analysis was performed using SPSS.25.

RESULTS

We obtained a total simple of 93 patients, mostly male (59%) and with a mean age of 56.99 years (SD 12. 65). The mean time since transplantation was 4.45 years, with the majority being bilateral (81.7%) and mostly due to chronic obstructive pulmonary disease (37.6%) and diffuse interstitial lung disease (29%). Baseline clinical data and sample information from our population are included in table 1 .

Table 1

Sample characteristics

VARIABLES	SAMPLE RESULTS
Sex	• Women: 37 (40.9%) • Males: 56 (59.1%)
Age	Mean 56.99 años, SD 12.65.
Time since transplantation	Mean 4.45 años, SD 3.71.
Type of transplant	• Unilateral 17(18.3%) • Bilateral 76(81.7%)
Disease leading to transplantation	• Chronic obstructive pulmonary disease: 35 (37.6%) • Diffuse interstitial lung disease: 27 (29%) • Pulmonary hypertension: 18 (19.4%) • Cystic fibrosis: 10 (10.8%) • Other: 3 (3.2%)

The most commonly administered vaccine was Spikevax from Moderna (93%), with anti-spike IgG in 27% of patients, with a median antibody levels of 4.81 BAU/ml [4.81-71.60]).

Thirteen patients (14%) were infected with SARS-CoV2, without generating natural immunity (anti-nucleoprotein IgG) in 38%. Of these, 7 became infected post-vaccination (5 of them despite having anti-spike IgG), with a median time from 2nd dose to infection of 2.6 months. Neither older age (comparing the 75th percentile with the rest), nor higher immunosuppression (analyzed by anticalcineurin levels in the most recent sample before vaccination, number of infections in the last year and the presence of neoplasias) influenced the generation of immunity (table 2 ).

Table 2

Analysis of immunity with respect to degree of immunosuppression and age.

VARIABLE	INMUNITY(Antibodies yes vs. no)
	(X square)	P value
Anticalcineurinic levels (adequate vs. elevated)*	1.184		0.553
Infections in the last year (none vs. More than one)	0.019		0.891
Existence of neoplasias (no vs. yes)	0.431		0.512
Age (in quartiles)	2.920		0.404

*Adequate levels of anticalcineurinic drugs are 15-18 ng/ml for the first six months, 10-15 ng/ml from 6-12 months and 7-8 ng/ml from 12 months onwards.

DISCUSSION

Our study demonstrates greater humoral immunity in LT than in previous studies, using the Moderna laboratory vaccine versus Pfizer. It is also the first to analyze whether the degree of immunosuppression and age in LT influence the vaccine response, indicating that there is no such relationship.

In our LT sample, the majority of patients received an mRNA vaccine (Moderna laboratory), with immunity being achieved 4 months after administration of the 2nd dose in 27% of the patients. The median antibody title was 4.81 BAU/ml, far from the values considered protective (>34 BAU/ml).

Despite vaccination, 7 patients became infected with SARS-CoV2, 2.6 months after the 2nd dose, including 5 of them with protective levels of anti-spike antibodies, demonstrating suboptimal efficacy of the vaccine antibodies.

Since a lower response to other vaccines reported in elderly people (7), we compared the antibody levels at the 75th percentile of the sample with the rest, without finding significant differences. We also assessed whether greater immunosuppression, as measured by supratherapeutic levels of anticalcineurinic before vaccine, the presence of neoplasias or more than one infection in the last year influenced the vaccine response, without finding any differences.

Studies of the SARS-CoV2 vaccine in LT have so far only taken into account the results after administration of two doses, as in our study. In an Austrian study, with a small sample (12 LT), no humoral immunity was observed after the administration of 2 doses of the Pfizer laboratory vaccine in any patient (5), while in an Israeli study of 168 LT, also carried out with Pfizer, humoral immunity was observed in 18% (6). In our sample, we observed a higher immunity, 27%, although our sample was intermediate between the two studies and the vaccine administered in most of them was another, that of the Moderna laboratory. There are studies in immunocompetent patients, such as one by Klein (7), one by Boyarsky (8) and another by Narasimhan (9), which show greater humoral immunity in patients who received the Moderna vaccine compared to the Pfizer vaccine, which could explain our better results compared to previous studies in LT.

In the previously mentioned studies in LT (5,6), it was not analysed whether high immunosuppression or older age influenced the vaccine response. However, studies in immunocompetent (7) patients have shown that older patients develop low humoral immunity. This relationship was not demonstrated in our study either.

On the other hand, it has the limitations of being a small simple study and having been conducted with only two doses of vaccine.

To confirm the greater efficacy of the vaccine from the Moderna laboratory, it would be interesting to analyze several groups of LT in which the different types of existing vaccines against SARS-CoV2, as well as to analyze cellular immunity and not only humoral immunity.

We conclude that vaccination against SARS-CoV2 in LT generates limited and ineffective immunity with only 2 doses. It is possible that these patients may require periodic doses to ensure better immunity; in fact, 4 doses have already been administered in these patients in Spain. It would be important to conduct studies after administration of more doses to verify this.

Financial support and sponsorship

None declared.

REFERENCES

1. Scharringa S, Hoffman T, van Kessel DA, et al. Vaccination and their importance for lung transplant recipients in a COVID-19 world. Expert Rev Clin Pharmacol. 2021;14(11):1413-1425.

2. Mohammed AH, Blebil A, Dujaili J, et al. The Risk and Impact of COVID-19 Pandemic on Immunosuppressed Patients: Cancer, HIV, and Solid Organ Transplant Recipients. AIDS Rev. 2020;22(3):151-157.

3. Messika J, Eloy P, Roux A, et al. COVID-19 in Lung Transplant Recipients. Transplantation. 2021;105(1):177-186.

4. Umakanthan S, Sahu P, Ranade AV, et al. Origin, transmission, diagnosis and management of coronavirus disease 2019 (COVID-19). Postgrad Med J. 2020;96(1142):753-758.

5. Havlin J, Svorcova M, Dvorackova E, et al. Immunogenicity of BNT162b2 mRNA COVID-19 vaccine and SARS-CoV-2 infection in lung transplant recipients. J Heart Lung Transplant. 2021;40(8):754-758.

6. Shostak Y, Shafran N, Heching M, et al. Early humoral response among lung transplant recipients vaccinated with BNT162b2 vaccine. Lancet Respir Med. 2021;9(6):52-53.

7. Klein S, Pekosz A, Park HS, et al. Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma donor population. J Clin Invest. 2020;130(11):6141-6150.

8. Boyarsky BJ, Werbel WA, Avery RK, et al. Immunogenicity of a single dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients. JAMA. 2021;325(17):1784–1786.

9. Narasimhan M, Mahimainathan L, Clark AE, et al. Serological response in lung transplant recipients after two doses of SARS-CoV-2 mRNA vaccines. bioRxiv. 2021.

Conflicts of Interest

The authors have no conflicts of interest to declare.