Since their conception with the smallpox vaccine, vaccines used worldwide have mitigated multiple pandemics, including the recent COVID-19 outbreak. Insightful studies have uncovered the complexities of different functional networks of CD4 T cells (T helper 1 (Th1); Th2, Th17) and CD8 T cells (T cytotoxic; Tc), as well as B cell (B^IgM, B^IgG, B^IgA and B^IgE) subsets, during the response to vaccination. Both T and B cell subsets form central, peripheral, and tissue-resident subsets during vaccination. It has also become apparent that each vaccination forms a network of T regulatory subsets, namely CD4+ CD25+ Foxp3⁺ T regulatory (Treg) cells and interleukin-10 (IL-10)-producing CD4+ Foxp3⁻ T regulatory 1 (Tr1), as well as many others, which shape the quality/quantity of vaccine-specific IgM, IgG, and IgA antibody production. These components are especially critical for immunocompromised patients, such as older individuals and allograft recipients, as their vaccination may be ineffective or less effective. This review focuses on considering how the pre- and post-vaccination Treg/Tr1 levels influence the vaccination efficacy. Experimental and clinical work has revealed that Treg/Tr1 involvement evokes different immune mechanisms in diminishing vaccine-induced cellular/humoral responses. Alternative steps may be considered to improve the vaccination response, such as increasing the dose, changing the delivery route, and/or repeated booster doses of vaccines. Vaccination may be combined with anti-CD25 (IL-2Rα chain) or anti-programmed cell death protein 1 (PD-1) monoclonal antibodies (mAb) to decrease the Tregs and boost the T/B cell immune response. All of these data and strategies for immunizations are presented and discussed, aiming to improve the efficacy of vaccination in humans and especially in immunocompromised and older individuals, as well as organ transplant patients.

We examined what happened during a 6‐year period to 1121 end‐stage renal disease patients who registered with their willing/incompatible living donors for kidney exchanges with the Alliance for Paired Donation (APD). Of all patients, 65% were transplanted: 37% in kidney paired donation (APD‐KPD, APD‐other‐KPD); 10% with compatible live donors (APD‐LD); and 18% with deceased donors (APD‐DD). The remaining patients were withdrawn (sick/died/others; 15%), or were still waiting (20%). For those patients with a cPRA 0–94%, 72% received a transplant. In contrast, only 49% of very highly sensitized (VHS; cPRA 95–100%) were transplanted. Of the VHS patients, 50% were transplanted by KPD/APD‐LD while 50% benefited through prioritization of deceased donors in the modified kidney allocation system (KAS introduced in 2014). All APD transplanted groups had similar death‐censored 4‐year graft survivals as their relevant Organ Procurement and Transplantation Network (OPTN) groups. It is noteworthy that VHS graft and patient survival results were comparable to less sensitized and nonsensitized patients. All patients should be encouraged to search for compatible donors through different options. Expanding the donor pool through KPD and the new KAS of the OPTN increases the likelihood of transplantation for VHS patients.

HLA matching improves long-term outcomes of kidney transplantation, yet implementation challenges persist, particularly within the African American (Black) patient demographic due to donor scarcity. Consequently, kidney survival rates among Black patients significantly lag behind those of other racial groups. A refined matching scheme holds promise for improving kidney survival, with prioritized matching for Black patients potentially bolstering rates of HLA-matched transplants. To facilitate quantity, quality and equity in kidney transplants, we propose two matching algorithms based on quantification of HLA immunogenicity using the hydrophobic mismatch score (HMS) for prospective transplants. We mined the national transplant patient database (SRTR) for a diverse group of donors and recipients with known racial backgrounds. Additionally, we use novel methods to infer survival assessment in the simulated transplants generated by our matching algorithms, in the absence of actual target outcomes, utilizing modified unsupervised clustering techniques. Our allocation algorithms demonstrated the ability to match 87.7% of Black and 86.1% of White recipients under the HLA immunogenicity threshold of 10. Notably, at the lowest HMS threshold of 0, 4.4% of Black and 12.1% of White recipients were matched, a marked increase from the 1.8% and 6.6% matched under the prevailing allocation scheme. Furthermore, our allocation algorithms yielded similar or improved survival rates, as illustrated by Kaplan–Meier (KM) curves, and enhanced survival prediction accuracy, evidenced by C-indices and Integrated Brier Scores.

Immunosuppressed kidney transplant (KT) recipients produce a weaker response to COVID-19 vaccination than immunocompetent individuals. We tested antiviral IgG response in 99 KT recipients and 66 healthy volunteers who were vaccinated with mRNA-1273 Moderna or BNT162b2 Pfizer-BioNTech vaccines. A subgroup of participants had their peripheral blood leukocytes (PBLs) evaluated for the frequency of T helper 1 (Th1) cells producing IL-2, IFN-γ and/or TNF-α, and IL-10-producing T-regulatory 1 (Tr) cells. Among KT recipients, 45.8% had anti-SARS-CoV-2 IgG compared to 74.1% of healthy volunteers (p = 0.009); also, anti-viral IgG levels were lower in recipients than in volunteers (p = 0.001). In terms of non-responders (≤2000 U/mL IgG), Moderna’s group had 10.8% and Pfizer-BioNTech’s group had 34.3% of non-responders at 6 months (p = 0.023); similarly, 15.7% and 31.3% were non-responders in Moderna and Pfizer-BioNTech groups at 12 months, respectively (p = 0.067). There were no non-responders among controls. Healthy volunteers had higher Th1 levels than KT recipients, while Moderna produced a higher Th1 response than Pfizer-BioNTech. In contrast, the Pfizer-BioNTech vaccine induced a higher Tr1 response than the Moderna vaccine (p < 0.05); overall, IgG levels correlated with Th1(fT_TNF-α)/Tr1(fT_IL-10) ratios. We propose that the higher number of non-responders in the Pfizer-BioNTech group than the Moderna group was caused by a more potent activity of regulatory Tr1 cells in KT recipients vaccinated with the Pfizer-BioNTech vaccine.

Since its conception with the smallpox vaccination, worldwide-used vaccines have thwarted multiple pandemics including the recent COVID-19 outbreak. Insightful studies uncovered complexities of different functional networks of CD4 T cells [T helper 1 (Th1); Th2, Th17] and CD8 T cells (T cytotoxic; Tc) as well as B cells (BIgM, BIgG, BIgA and BIgE) subsets during response to vaccination. Both T and B cell subsets forge central, peripheral and tissue-resident subsets during vaccination. It also became apparent that each vaccination formed the network of T regulatory subsets, namely CD4+CD25+Foxp3+ T regulatory (Treg) cells and interleukin-10 (IL-10)-producing CD4+Foxp3− T regulatory 1 (Tr1) as well as many others, are shaping the quality/quantity of vaccine-specific IgM, IgG, and IgA antibody production. These components are especially critical for immunocompromised patients, such as older individuals and allograft recipients, as their vaccination may be ineffective or less effective. This review focuses on presenting how pre- and post-vaccination Treg/Tr1 levels influence the vaccination efficacy. Experimental and clinical work revealed that the Treg/Tr1 involvement evoked different immune mechanisms in diminishing vaccine-induced cellular/humoral responses. Alternative steps may be considered to improve the vaccination response by increasing a dose, changing the delivery route and/or repeated booster doses of vaccines. Vaccination may be combined with anti-CD25 (IL-2Ra chain) or anti-PD-1 (programmed cell death protein) monoclonal antibody (mAb) to decrease Tregs and boost the T/B cell immune response. All these data and strategies for immunizations are presented and discussed, aiming to improve the efficacy of vaccination in humans and especially in immunocompromised and older individuals as well as organ transplant patients.