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Table of Contents
Year : 2022  |  Volume : 16  |  Issue : 1  |  Page : 17-25

On the way to mandate booster vaccine dose of coronavirus disease 2019 for transplant recipients: A narrative review of literature

1 Department of Nephrology, Institute of Kidney Diseases and Research Center, Dr. HL Trivedi Institute of Transplantation Sciences, Ahmedabad, Gujarat, India
2 Department of Infectious Diseases, Sterling Hospital, Ahmedabad, Gujarat, India
3 Department of Nephrology, Osmania Medical College, Hyderabad, Telangana, India

Date of Submission08-Jan-2022
Date of Acceptance11-Feb-2022
Date of Web Publication03-Mar-2022

Correspondence Address:
Prof. Vivek B Kute
Department of Nephrology, Institute of Kidney Diseases and Research Center, Dr. HL Trivedi Institute of Transplantation Sciences, Ahmedabad, Gujarat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijot.ijot_7_22

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Coronavirus disease 2019 (COVID-19) vaccine efficacy, especially against severe disease is known to wane over time. We examined current knowledge of COVID-19 vaccine booster dose in solid organ transplant recipients (SOTR). We have systematically searched PubMed, EMBASE, MEDLINE, Scopus and Google Scholar with the following MeSH terms: “SARS-CoV-2 vaccine,” or “COVID-19 vaccine,” and “organ transplantation” and “booster” or “third dose.” This review article examines a number of studies including guidelines from professional societies examining the safety as well as increased immunogenicity of a booster dose among SOTR. Equitable distribution of vaccines across the globe is the need of the hour. While some countries are well into the booster dose phase, the lower-income countries are languishing behind with primary doses for their health workers. Available reports suggest less efficacy of COVID-19 vaccine in SOTR suggesting booster dose for them. Several studies highlighted the safety and efficacy of COVID-19 vaccines booster dose among SOTR. SOTR should also continue to adhere to all safety and COVID-19 appropriate behaviors. There is a growing need for alternative strategies to improve protection. As Omicron cases rise around the world, India announced that COVID-19 vaccination for children aged 15–18 years and “precautionary (booster) doses” would be administered to healthcare and frontline workers and people above 60 years of age with comorbidities from January 2022. In near future, with increased availability of vaccinations, all SOTR will have access to booster dose in a phased manner.

Keywords: Booster dose, coronavirus disease 2019 vaccine, solid organ transplant

How to cite this article:
Kute VB, Desai SN, Meshram HS, Shah KN, Chauhan S, Mishra VV, Sahay M. On the way to mandate booster vaccine dose of coronavirus disease 2019 for transplant recipients: A narrative review of literature. Indian J Transplant 2022;16:17-25

How to cite this URL:
Kute VB, Desai SN, Meshram HS, Shah KN, Chauhan S, Mishra VV, Sahay M. On the way to mandate booster vaccine dose of coronavirus disease 2019 for transplant recipients: A narrative review of literature. Indian J Transplant [serial online] 2022 [cited 2022 May 29];16:17-25. Available from: https://www.ijtonline.in/text.asp?2022/16/1/17/338987

  Introduction Top

As on January 8, 2022, India leads the way in large-scale coronavirus disease 2019 (COVID-19) vaccination of the population with 1,485,958,323 doses given already (858,323,079 first dose and 627,635,244 s dose in 18 + years population and 20,234,580 first dose in the age group of 15–18 years).[1] India reported 141,986 new COVID-19 cases on January 8, 2022.Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the most effective way of protecting against the development of severe COVID-19 disease, as observed in large phase III trials as well as in real-life experience.[2],[3] Vaccination against SARS-CoV-2 seems to be the only way to attain herd immunity, and thereby reduce community transmission of SARS-CoV-2 in the population. Recent studies have reported equivalent[4] or less protection[5],[6] from natural immunity in COVID-19 recovered versus fully vaccinated persons. After the administration of a single dose of vaccine, the humoral response against SARS-CoV-2 in persons with a history of SARS-CoV-2 infection is greater than the response in previously uninfected participants who have received a second dose.[7] The Centers for Disease Control and Prevention (CDC) continues to recommend COVID-19 vaccination for all eligible persons, including those who have been previously infected with SARS-CoV-2.

  Methods Top

This review article examines a number of studies examining the safety as well as increased immunogenicity of a booster with a third dose of the mRNA vaccine among solid organ transplant recipients (SOTR). We have systematically searched the search engine of PubMed, Google Scholar, MEDLINE, EMBASE, Scopus, WHO portal for COVID-19 research with the following MeSH terms: “SARS-CoV-2 vaccine,” or “COVID-19 vaccine,” and “organ transplantation” and “booster” or “third dose.” Two independent investigators (SD, HSM) have performed the literature search, and the senior investigator (VK, MS) cross-checked the validity of the included study. We have included all the studies irrespective of the date of electronic availability till December 17, 2021. There were no filters for the type of article, and we have included the letter to editors and comments as well. There was no cut-off sample size for inclusion. As the data are scarce, we have included all grades of evidence. There were no restrictions to language in our search. Online and ahead of prints were included. The results were displayed in tabular forms with the author's name, geographic region, sample size, vaccine studied, results, and additional remarks retrieved from the study. During our literature search, we have also searched for the guidelines pertaining to booster dose, published by various professional bodies, and the results were summarized briefly. No statistical procedure was applicable for the study. In view of rapidly evolving data related to COVID-19, there are some chances of missing data during manuscript drafting.

  Rationale for Booster Doses Top

Vaccine efficacy, especially against severe disease is known to wane over time (i.e., waning immunity).[8] A recent systematic review and meta-regression analysis[9] demonstrated that across the four WHO EUL COVID-19 vaccines with the most data (i.e., BNT162b2, mRNA 1273, Ad26.COV2.S, and ChAdOx1-S vaccine), vaccine effectiveness against severe COVID-19 decreased by about 8% over a period of 6 months in all age groups. The decrease in vaccine effectiveness against severe disease was reported to be as high as 32% in adults over 50 years of age. Viral genomes are continually undergoing genetic drifting and shifting, thereby giving rise to new strains or variants. Routine doses of vaccines may not provide optimal protection against new variants of concern such as the Indian Delta variant or the African Omicron variant. Studies have conclusively suggested that the currently recommended primary series of vaccination (2 doses) provide suboptimal protection to SOTR. The Director-General of WHO has called for a moratorium on booster vaccination for healthy adults until the end of 2021 to counter the persisting and profound inequity in global vaccine access. Equitable distribution of vaccines across the globe is the need of the hour. While some countries are well in to the additional/booster dose phase, the lower-income countries are languishing behind with primary doses for their health workers and citizens.[1]At least 126 countries worldwide have already issued recommendations on booster or additional vaccination and more than 120 have started programmatic implementation. The majority of these countries are classified as high-income or upper middle-income. No low-income country has yet introduced a booster vaccination program. The most commonly prioritized target populations for booster doses are older adults, health workers and immunocompromised individuals. The decision to recommend and implement a booster dose is complex and requires, beyond clinical and epidemiological data, a consideration of national strategic and programmatic priorities, and importantly an assessment of the prioritization of globally limited vaccine supply. Additional considerations include optimal timing of the booster dose, consideration of homologous versus heterologous boosters, possibility for dose-sparing for booster doses, booster needs in previously infected individuals, specification and prioritization of high-risk populations, programmatic feasibility and sustainability as well as promotion of global equity.

SOTR by virtue of being on multiple immunosuppressive medications for a considerable period, elicit reduced immunogenicity to nearly all vaccines, due to decreased lymphocyte activation, interaction with antigen-presenting cells, and diminished B-cell memory responses.[10] Extensive experience with the use of influenza vaccine in SOTR have shown that antibody and cell-mediated immune responses are lower as compared with the general population.[11],[12] This reduced efficacy notwithstanding, influenza vaccines have successfully reduced influenza-associated complications in SOTR.[13],[14] While data are still being generated, current evidence suggest that the immunogenicity of SARS-CoV-2 vaccine is also suboptimal in SOTR.[15] Studies demonstrating reduced efficacy of SARS-CoV-2 vaccines among SOTR are emerging, however the extent of reduction of efficacy is not yet defined. SOTR vaccinated against COVID-19 can still develop severe, and even critical, COVID-19 disease.[16] Indian studies have also shown less efficacy of COVID-19 vaccine in SOTR.[17],[18] SOTR should therefore continue to adhere to all safety and COVID-19 appropriate behaviors and hygienic measures.

SOTR having COVID-19 infection suffer from higher morbidity as well as mortality as compared to general population.[19],[20] As observed in a case series by Azzi et al.,[21] SOTR are predisposed to a higher rate of life-threatening complications: ICU admission ranged from 9% to 61%, respiratory failure requiring intubation from 27% to 39%, and acute kidney failure from 30% to 89%. This is largely because of the high prevalence of associated comorbid conditions such as diabetes, hypertension, coronary artery disease, obesity and renal dysfunction in these patients. Comorbidities rather than immunosuppression intensity were the main risk factors for impaired outcome in a large cohort.[22] The efficacy of the current mRNA vaccines for protection from COVID-19 in the general population is reported between 92% and 95%.[1],[2] Accordingly, these vaccines have been shown to elicit strong antibody as well as T cell responses.[23]

In the initial studies published to date among SOTR, mRNA vaccines mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) elicited significantly suboptimal antibody responses compared with controls. The rate of seroconversion ranged from 5% to 58.8%, while the antibody titers remained significantly lower in comparison to general population.[8],[24],[25],[26] Kidney transplant recipients (KTR) treated with belatacept demonstrated even lower seroconversion rates (5%) following mRNA vaccines. This finding was not affected by the timing between vaccination and belatacept administration.[27],[28] Longer time from transplantation and better kidney function was associated with higher immunogenicity in one study in KTRs.[29] In a study analyzing the two mRNA vaccines, antibody response after mRNA-1273 was higher as compared with BNT162b2 (60% vs. 48%, respectively).[13] However, the clinical significance of this finding could not be ascertained and hence both vaccines are equally recommended posttransplant. A number of studies have now reported increased immune response with a third booster dose of the mRNA vaccine, which elicited an antibody response in 47%–68% recipients and also reported higher mean antibody titers in the recipients.[30],[31]

Although data regarding T-cell responses following immunization in SOTR is insufficient, it has been reported that T-cell responses are comparable to the control population.[32],[33] In a study of renal transplant patients, antibody response to mRNA vaccine remained poor, but >80%–90% of patients mounted sufficient CD4+ and CD8+ T-cell responses.[34] However, despite the T-cell response, there was diminished cytokine production and activation. Chavarot et al. reported a T-cell response for the SARS-CoV-2 vaccine in only 2/40 patients (5%) on day 28 and in 7/23 patients (30%) 30 days after the second dose of the Pfizer BNT162b2 vaccination in a cohort of 101 KTR treated with betalacept.[15]

A testament to the efficacy of current vaccines in SOTR is a recent study from the UK, which showed that mortality from COVID-19 was reduced from 12.0%–12.6% to 7.7% among those who had received two doses of vaccine, compared with those who were unvaccinated or those patients who had only received a single vaccine dose, respectively.[35]

Qin et al.[36] reported a higher frequency of breakthrough infections among vaccinated SOTR. As compared to controls, SOTR were found to have an 82 times greater rate of breakthrough infection. Also, the transplant cohort reported a 485-fold higher risk of severe breakthrough disease leading to hospitalization and death. Wadei et al.[37] recently reported seven postkidney transplant patients with undetectable or low titer antibodies who developed COVID-19 infection after receiving 1 or 2 doses of the SARS-CoV-2 mRNA vaccine. In a single centre case series in California, Keehner et al. reported a postvaccination infection rate of 0.6% among SOT recipients, as compared to 0.05% in control population.[38] Therefore, it can be concluded that although mRNA vaccines are highly effective in protecting SOT recipients from symptomatic COVID-19, the degree of protection is lesser than that offered to the general population. This brings the need of a subsequent booster dose or a third primary dose of the mRNA-based SARS-CoV-2 vaccine for post SOTR for effective protection against symptomatic COVID-19.

Several other studies highlighting the safety and efficacy of the third primary dose/booster dose of SARS-CoV-2 mRNA vaccines among SOTR are summarized in [Table 1].
Table 1: Safety and efficacy of third primary dose/booster dose of SARS-CoV-2 mRNA vaccines among solid organ transplant recipients

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Hall et al.[39] reported a double-blind, randomized, controlled trial of a third dose of mRNA-1273 vaccine (Moderna) as compared with placebo in 120 patients without prior history of COVID-19. Patients were either given Moderna mRNA vaccine or saline placebo 2 months after the second dose of vaccination. The primary outcome was a serologic response characterized by an anti–receptor-binding domain (RBD) antibody level of at least 100 U per mL at month 4. COVID-19 developed in 1 patient in the placebo group. At month 4, an anti-RBD antibody level of at least 100 U per mL was present in 33 of 60 patients (55%) in the mRNA-1273 group and in 10 of 57 patients (18%) in the placebo group. After the third dose, the median percent virus neutralization was 71% in the mRNA-1273 group and 13% in the placebo group. This study successfully demonstrated a third dose of vaccine conferred substantially greater immunogenicity in SOTR.

In August 2021, Kamar et al.[30] reported the humoral response in a group of 101 consecutive SOTR (mean [±standard deviation] age, 58 ± 2 years; 69% were men) who were given three doses of the messenger RNA vaccine BNT162b2 (Pfizer–BioNTech). Median time between second and third dose was 61 days. The time between transplantation and the initiation of vaccination was 97 ± 8 months. The prevalence of antibodies was measured before each of the three doses in all patients. The prevalence of anti–SARS-CoV-2 antibodies was 0% before the first dose, 4% (95% confidence interval [CI], 1–10; 4 of 101 patients) before the second dose, 40% (95% CI, 31–51; 40 of 99 patients) before the third dose, and 68% (95% CI, 58–77; 67 of 99 patients) 4 weeks after the third dose. Out of 59 seronegative patients before the third dose, 26 (44%) became seropositive 4 weeks after the booster dose. Also antibody titres of those tested seropositive after second dose increased substantially after the third dose-from 36 ± 12 before the third dose to 2676 ± 350 1 month after the third dose (P < 0.001). None of the patients developed COVID-19 after the administration of third dose. This study showed that administration of a third dose of the BNT162b2 vaccine to solid-organ transplant recipients significantly improved the immunogenicity of the vaccine.

Peled et al.[40] reported the immunogenicity and safety of a third booster dose of the Pfizer BNT162b2 vaccine in 96 heart transplant patients given 168 days after the second dose. No serious adverse events were recorded. There were no documented episodes of rejection following the third dose. After 18 days of the booster dose, patients showing a positive antibody titer increased from 23% to 67%. A corresponding increase in the neutralizing capacity of the antibodies was also noted. Also a significant increase in the IgG anti-RBD antibody titers was reported – which was >3 times that reported after the second dose.

The earliest study of its kind was performed by Benotmane et al. in May 2021 in France where they investigated the antibody responses to a third dose of the mRNA-1273 SARS-CoV-2 vaccine among KTR who had not shown response to 2 doses of the vaccine.[41] 159 KTR, who had an anti-spike IgG levels less than an arbitrary cut-off of 50 AU/mL were given a third dose of the mRNA-1273 (Moderna) vaccine, a median of 51 days after the second dose. After a median period of 28 days of third dose, 78 patients (49%) had antibody titers >50 AU/mL. Stronger titers were reported in patients who had a weak response after second dose, than those who had no response after the two doses. In addition, patients taking tacrolimus, mycophenolate, and steroids were less likely to develop anti-SARS-CoV-2 antibodies than those treated with other regimens.

Werbel et al.[31] reported a case series from John Hopkins Hospital, USA, including 30 SOTR who were given a third dose of vaccine after showing suboptimal antibody response to first two doses of the vaccine. Among the chosen patients, 24 patients had a negative antibody response and 6 had a weak response following two routine doses of the vaccine. The booster dose was given a median of 67 days after the second dose. All 6 patients who had an initial weak response showed a strong antibody response after the third dose. Among patients with a negative initial response, 25% developed high antibody titers and 8% developed low antibody titers 14 days after the third dose. One heart transplant recipient developed an acute antibody mediated rejection on day 7 of the third dose.

Karaba et al.[42] reported national prospective, observational cohort of 47 SOTR for clinical and research anti-spike IgG, pseudoneutralization, and live-virus neutralization against variant of concern before and after a third COVID-19 vaccine dose with comparison to 15 healthy controls after two mRNA vaccine doses. The antibody response was significantly lower in SOTR than healthy controls. Marlet et al.[43] reported a retrospective study to characterize antibody responses induced by a third dose of mRNA COVID-19 vaccine in 160 KTR. The prevalence of anti-spike IgG ≥30 BAU/mL after the third dose was 39% in KTR and better response in younger patients and those with a history of COVID-19. Kumar et al.[44] reported secondary analysis of a randomized, double-blind, controlled trial of a third dose of mRNA-1273 vaccine versus placebo in single-center transplant program in 117 SOTR (60 in the mRNA-1273 group and 57 in the placebo group). They assessed neutralizing antibody responses against SARS-CoV-2 variants in transplant recipients after 2 and 3 vaccine doses. There was no clear correlate of protection for neutralizing antibody. Chavarot et al.[45] investigated vaccine immunogenicity in 62 belatacept-treated KTR with prior COVID-19 Administration of a third dose of BNT162b2 mRNA COVID-19 vaccine did not improve immunogenicity in KTRs treated with belatacept without prior COVID-19. Seroprevalence after three-vaccine doses in 35 nonbelatacept-treated KTRs was 37.1%. Westhoff et al.[46] reported 10 KTR under immunosuppression without measurable SARS-CoV-2 spike antibodies 4 weeks after a second dose of BNT162b2 (Pfizer–BioNTech) received a third vaccine dose (mRNA-1273; Moderna), The third dose of an mRNA vaccine elicits a humoral and cellular response in 60% and 90% of KTR patients, respectively, who failed the primary vaccination. Massa et al.[47] reported a prospective longitudinal study in 61 KTR given three doses of the BNT162b2 COVID-19 vaccine. A third dose of the BNT162b2 vaccine increases both cross-variant neutralizing antibody and cellular responses in KT recipients with an acceptable tolerability profile.

Havlin et al.[48] reported 15 lung transplant recipients without a history of SARS-CoV-2 infection who received 2 doses of the BNT162b2 vaccine 21 d apart with no antibody response. In the absence of humoral response, they detected emergence of cellular response in 47% of LTRs after the third vaccine dose, which might have a clinical benefit; however, the measurable response is low, dominantly cellular, and only detectable in half of the patients. Noble et al.[49] reported that belatacept significantly reduced the immune response to SARS-CoV-2 mRNA vaccination; however, delaying SARS-CoV-2 vaccination until 21 d after a belatacept infusion may improve immunogenicity. Alejo et al.[50] reported the first series describing the antibody response among SOTR after 4 doses of vaccine against COVID-19 and support continued exploration of subsequent vaccine doses in SOTR.

The gap between last dose and booster dose is important, and shortening the gap for SOT, is a theoretically promising way. Currently, in Indian settings, this gap is 9 months, and in Western world where mRNA vaccine predominates, it is around 5 months. The research conducted so far has used variable gaps after the last dose, and this area is a matter of further search.

Safety profile of booster dosing in SOT would be an important aspect. Anecdotal reports of safety issues have been reported with COVID-19 vaccine previously, but effect and causation were not established. Grossly, so far, all types of COVID-19 vaccines have shown considerable safety, even with booster doses[51] and no major safety issues has been raised with any of the vaccine.

In the Indian scenario, the booster regimen is incorporated for aged above 60 years only, and there are no governmental recommendations for booster dosing in SOT. Hence, there are no available data for Indian ethnicity yet. However, reports from Indian studies of 2 dose schedule[17],[18] showed lower immunogenicity in SOT, which calls for a booster dose. In addition, there are data of improvement of immune response after booster dose with Oxford vaccine, from other parts of the world.[52],[53] Hence, this becomes obvious that implementation of booster for SOT, in Indian settings would also yield good results.

  Recommendations from Professional Societies Top

After April 2021, since more and more data regarding suboptimal efficacy of mRNA vaccines in immunocompromised patients started emerging and definite evidence in favor of third primary or booster dose of vaccine surfaced, a number of health authorities and governments have come forward and recommended third dose of vaccine to SOTR. Booster dose for all immunosuppressed patients has also been incorporated into standard policy and guidelines in several countries.

  The Transplantation Society Top

A third-dose booster of mRNA COVID-19 vaccine should be considered, where allowed by local regulatory approval. There is insufficient data to recommend boosters of patients who have not received mRNA vaccines at this time.[54]

  Centre for Disease Control and Prevention Top

Moderately or severely immunocompromised persons aged ≥12 years (Pfizer-BioNTech vaccine recipients) or ≥18 years (Moderna or Pfizer-BioNTech recipients) should receive an additional primary dose of the same mRNA COVID-19 vaccine administered for the primary series ≥28 days after completion of the initial 2-dose series.[55] Currently, CDC does not recommend an additional primary dose for children aged 5–11 years with moderate or severe immune compromise.

  American Society of Transplantation Top

Based on the current evidence, we recommend providing a third dose of mRNA vaccine for SOTR that have previously completed a 2-dose mRNA vaccine series if local regulations allow; The use of a third dose should, until further evidence is available, be based on individual patients' unique situation and must depend on local availability of vaccines and local regulations.[56]

  National Health Service, United Kingdom Top

Two doses of vaccine, regardless of type, in solid organ transplant and islet recipients do not provide the same high level of protection against COVID-19 as for the general population. In the absence of any other health contraindication, transplant recipients and patients on the transplant waiting list are strongly encouraged to accept the full course of vaccination (currently three doses of vaccine) and any subsequent booster doses.[57] Among transplant recipients and patients waiting for a transplant, unvaccinated patients have a significantly increased chance of developing severe disease if they contract SARS-CoV-2 infection in comparison with vaccinated patients.

  Joint Committee on Vaccination and Immunization - United Kingdom Top

At the current time, Joint Committee on Vaccination and Immunization (JCVI) advises that a third primary dose be offered to individuals aged 12 years and over with severe immunosuppression in the proximity of their first or second COVID-19 vaccine doses in the primary schedule. For those aged 18 years and over, JCVI advises a preference for mRNA vaccines for the third primary dose, with the option of the AstraZeneca Vaxzevria vaccine for individuals who have received this vaccine previously where this would facilitate delivery. In exceptional circumstances, persons who received an mRNA COVID-19 vaccine previously may be offered a third primary dose of AstraZeneca Vaxzevria vaccine following a decision by a health professional on a case-by-case, individualized basis. For those aged 12–17 years the Pfizer-BNT162b2 vaccine remains the preferred choice.

  WHO Sets Stage for Coronavirus Disease 2019 Booster: Prioritize High-Risk Groups Top

Although experts believe that India should have begun boosting its frontline workers and vulnerable population by now, The Indian government expressed that vaccinating the adult population with both doses of the COVID-19 vaccine will be its first priority, ahead of booster doses. The additional advantage of booster dose to high-risk population cannot outweigh the benefit of wider coverage of community with primary vaccination doses.[58] Indeed, WHO has called for a moratorium on boosting until the benefits of primary vaccination have been made available to more people around the world The World Health Organisation suggested that introduction of booster doses should be “firmly evidence-driven” and “targeted” at population groups at highest risk of serious disease, and frontline healthcare workers. This WHO recommendation could serve as a catalyst for India to prioritize and make policy regarding administration of booster doses to the two priority groups.

In brief, from the experiences accumulated so far with booster dosing in SOT, we suggest that booster dosing would be helpful in increasing the immune response. Decreasing the gap between booster dosing, heterologous vaccine schedule, choosing higher potency COVID-19 vaccine, increased dose of COVID-19 vaccine, or regular interval dosing are attractive options, which needs further exploration for implementation in large scale.

In the Indian context, as Omicron cases rise in the country, and around the world, the nations announced COVID-19 vaccination for children aged 15 years which up will begin from January 3, 2022, and “precautionary doses,” or booster dose of COVID-19 vaccine, for healthcare/frontline workers and people above 60 years of age with co-morbidities from January 10, 2022. Hopefully in phased manner all SOTR will have access to booster dose of COVID-19 vaccine in India.

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Conflicts of interest

There are no conflicts of interest.

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