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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

TTV viral load as a predictor of antibody response to SARS COV-2 vaccination

Published:November 06, 2022DOI:https://doi.org/10.1016/j.healun.2022.10.025
      The measure of torquetenovirus (TTV) viremia is widely recognized as an optimal biomarker of an individual immune status. In the context of COVID-19, the predictive role of TTV load with regard to vaccine response has also been demonstrated, suggesting other intriguing applications for this widespread anellovirus.

      Keywords

      Torquetenovirus (TTV), a widespread anellovirus recognized as the main component of the healthy human virome, displays viremia that is highly susceptible to variations in immune competence. In general, higher viremias are associated with poor immune competence (e.g., causing opportunistic infections), while lower viremias are associated with hyperactive immune system (e.g., causing allograft rejection). In COVID-19, the applications of TTV monitoring is dual.
      The first aspect is the correlation between the TTV loads and prognosis, which is rather controversial. Querido et al reported a kidney transplant recipient who had a TTV load of 5.6 log10 copies/ml, which increased to 7.9 log10 copies/ml on day 43 after the diagnosis of SARS-CoV-2 infection, when the patient seroreverted.
      • Querido S
      • Calça R
      • Weigert A
      • et al.
      Kinetics of torquetenovirus DNA load in a recent kidney transplant recipient with mild SARS-CoV-2 infection and a failed antibody response.
      Froque’ et al reported that COVID-19 patients with detectable TTV DNA had an increased risk of subsequently developing infectious events (HR 9.28) and a trend (p = 0.05) toward higher TTV DNA area under a curve between days 7 and 17 after intensive care unit (ICU) admission in patients who died, as compared to survivors.
      • Forqué L
      • Albert E
      • Giménez E
      • et al.
      Monitoring of Torque Teno virus DNAemia in critically ill COVID-19 patients: may it help to predict clinical outcomes?.
      In line with the fact that the most severe presentations of COVID-19 are due to an exaggerated immune response, Solis et al reported that the rate of severe cases was higher in patients with low TTV DNA load in plasma, considering a threshold of 700 copies/ml. In severe patients, SARS-CoV-2 viremia positivity rates were higher than those in mild-moderate cases at any time point. When combined, TTV DNA load and SARS-CoV-2 viremia allowed to predict the outcome of COVID-19 infection, with a higher risk (HR = 12.4) of ICU admission in patients with low TTV DNA load and positive SARS-CoV-2 viremia.
      • Solis M
      • Gallais F
      • Garnier-Kepka S
      • et al.
      Combining predictive markers for severe COVID-19: Torquetenovirus DNA load and SARS-CoV-2 RNAemia.
      Stincarelli et al reported that serum TTV DNA seems unrelated to COVID-19 severity, while TTV miRNA tth8 seems related.
      • Stincarelli MA
      • Baj A
      • Guidotti B
      • et al.
      Plasma Torquetenovirus (TTV) microRNAs and severity of COVID-19.
      At the other end of the spectrum, Emmel et al found that the 100-day survival rate in cancer patients who died from COVID-19 was significantly lower in the TTV-positive group than in the TTV-negative group (p = 0.0475), and that in the cancer TTV-positive group, those who died also had a higher load of TTV than those who did not die (p = 0.0097).
      • Emmel V
      • Gama B
      • de Paula A
      • Ferreira G
      • Binato R
      • Abdelhay E
      Can Torque teno virus be a predictor of SARS-CoV-2 disease progression in cancer patients?.
      Saliva is an alternative (more easily accessible than blood) biological sample for PCR methods: Mendes-Correa et al reported that the saliva TTV and nasal-oropharyngeal SARS-CoV-2 loads were correlated (p = 0.008), and the TTV level decreased as symptoms resolved in the SARS-CoV-2 infected group (p = 0.028), but remained unchanged in the SARS-CoV-2 negative controls.
      • Mendes-Correa MC
      • Tozetto-Mendoza TR
      • Freire WS
      • et al.
      Torquetenovirus in saliva: a potential biomarker for SARS-CoV-2 infection?.
      A second, more relevant, aspect is the predictive role of TTV load with regard to vaccine responses. Healthy individuals with a median baseline TTV load of 3.8 log10 copies/ml have an efficient immune response to the influenza vaccine 30 days after vaccination; more than 80% of healthy individuals with a median baseline TTV load of 4.1 log10 copies/ml have a response to hepatitis B vaccine when measured at day 90 after vaccination.
      • Maggi F
      • Tempestini E
      • Lanini L
      • et al.
      Blood levels of TT virus following immune stimulation with influenza or hepatitis B vaccine.
      In lung transplantation, Hoek et al showed an odds ratio (OR) of 0.54 (p < 0.0001) for response to the first mRNA-1273 vaccine dose,
      • Hoek RA
      • Verschuuren EA
      • de Vries RD
      • et al.
      High torque tenovirus (TTV) load before first vaccine dose is associated with poor serological response to COVID-19 vaccination in lung transplant recipients.
      while Gallais et al showed an adjusted OR of 17.8 (p = 0.001) for pre-vaccine TTV viral load ≥6.2 log10 copies/ml and response to third BNT162b2 vaccine dose among 173 SARS-CoV-2-naïve recipients.
      • Gallais F
      • Renaud-Picard B
      • Solis M
      • et al.
      Torque teno virus DNA load as a predictive marker of antibody response to a three-dose regimen of COVID-19 mRNA-based vaccine in lung transplant recipients.
      In kidney transplantation, Reindl-Schwaighofer et al showed OR = 0.92 for homologous (ChAdOx1) or heterologous third dose in 2-dose mRNA vaccine nonresponders.
      • Reindl-Schwaighofer R
      • Heinzel A
      • Mayrdorfer M
      • et al.
      Comparison of SARS-CoV-2 Antibody response 4 weeks after homologous vs heterologous third vaccine dose in kidney transplant recipients: a randomized clinical trial.
      No studies have been reported so far investigating TTV loads and COVID-19 vaccine responses in liver or hematopoietic stem cell transplantations. We have found that healthcare workers with a baseline TTV load equal to or below 3.4 log10 copies/ml of serum showed higher anti-Spike antibody levels when measured on day 30 after the first BNT162b2 vaccine dose (p < 0.001; data not shown).
      Compared to other solid organ transplant recipients, lung transplant recipients receive higher levels of immunosuppression and accordingly have reduced COVID-19 vaccine responses.
      • Boyarsky BJ
      • Werbel WA
      • Avery RK
      • et al.
      Antibody response to 2-Dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients.
      These findings suggest a continuum where the higher the immunosuppression, the better the correlation between the basal TTV loads and vaccine-elicited antibody responses. Rezahosseini et al suggested that TTV load can be used to identify the optimal moment for vaccination in patients under maintenance immunosuppression,
      • Rezahosseini O
      • Nielsen SD
      Torque-Teno virus to optimize timing of vaccination against severe acute respiratory syndrome coronavirus 2 in solid organ transplant recipients.
      and evidences published so far are strenghtening this intuition. Despite at this stage further and larger observational clinical trials are required to consolidate this hypothesis, TTV-driven vaccine boosts represent an intriguing opportunity to increase the response rate of immunocomprimised patients. In this regard, integration of a pilot trial within the Horizon2020-funded “TTV Guide Tx” project (https://www.ttv-guide.eu/) should be warranted, to assess utility in association with futher correlates of vaccine response. So far only advanced age,
      • Hoek RA
      • Verschuuren EA
      • de Vries RD
      • et al.
      High torque tenovirus (TTV) load before first vaccine dose is associated with poor serological response to COVID-19 vaccination in lung transplant recipients.
      mycophenolate use,
      • Gallais F
      • Renaud-Picard B
      • Solis M
      • et al.
      Torque teno virus DNA load as a predictive marker of antibody response to a three-dose regimen of COVID-19 mRNA-based vaccine in lung transplant recipients.
      ,
      • Tanner R
      • Starr N
      • Chan G
      • et al.
      Humoral response to SARS-CoV-2 adenovirus vector vaccination (ChAdOx1 nCoV-19 [AZD1222]) in heart transplant recipients aged 18 to 70 years of age.
      triple immunosuppression,
      • Reindl-Schwaighofer R
      • Heinzel A
      • Mayrdorfer M
      • et al.
      Comparison of SARS-CoV-2 Antibody response 4 weeks after homologous vs heterologous third vaccine dose in kidney transplant recipients: a randomized clinical trial.
      and more advanced stage of organ failure
      • Tanner R
      • Starr N
      • Chan G
      • et al.
      Humoral response to SARS-CoV-2 adenovirus vector vaccination (ChAdOx1 nCoV-19 [AZD1222]) in heart transplant recipients aged 18 to 70 years of age.
      are reliable predictors of vaccine responses, while there are discordant results for time since transplantation.
      • Hoek RA
      • Verschuuren EA
      • de Vries RD
      • et al.
      High torque tenovirus (TTV) load before first vaccine dose is associated with poor serological response to COVID-19 vaccination in lung transplant recipients.
      ,
      • Reindl-Schwaighofer R
      • Heinzel A
      • Mayrdorfer M
      • et al.
      Comparison of SARS-CoV-2 Antibody response 4 weeks after homologous vs heterologous third vaccine dose in kidney transplant recipients: a randomized clinical trial.

      Author contributions

      D.F. searched the literature and wrote the first draft. A.B., L.A., and F.N. provided raw data for the HCW cohort. F.M. revised the manuscript

      Disclosure statement

      The authors declare no conflict of interest related to this manuscript.

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