Significant Fade Of Neutralizing Antibodies And Stable Cellular Immunity in 4 Times COVID-19 Vaccinated Noninfected Compared To COVID-19 Convalescent And 3 Times Vaccinated Hemodialysis Patients

To the Editor:

COVID-19 breakthrough currently caused by the Omicron variant of concern (VOC) has been attributed to the antibody fade following SARSCoV-2 vaccination and a high number of mutations in the spike protein of Omicron VOC as compared with the spike protein of the wild-type vaccine. However, vaccination booster doses that highly increase wildtype–specific antibody titer can compensate for the reduced specificity for at least 3 months.1

Spike protein is a protein present on the surface of viruses, which can help viruses bind to host cells and invade cells, and is one of the key factors for many viruses to attack humans.

In terms of immunity, the human immune system mainly relies on two mechanisms in the process of resisting virus invasion, namely cellular immunity and humoral immunity. Among them, cellular immunity mainly attacks infected cells by activating immune cells (such as T cells and natural killer cells); while humoral immunity mainly relies on the function of antibodies to identify and neutralize pathogens that invade the body.

The relationship between spike protein and immunity can be reflected in the following aspects:

First of all, the spike protein is an important factor for virus invasion, and its existence makes the human immune system face greater challenges. Therefore, vaccine research targeting the spike protein has become one of the important directions in the current fight against viruses. Vaccination can allow the human immune system to better recognize and attack viruses.

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Secondly, the spike protein is an important structure on the surface of the virus, and its antigenicity (that is, the ability to generate an immune reaction with the human immune system) is very strong. Therefore, the recognition and neutralization of the spike protein by antibodies has become one of the important strategies against the virus. one. Some neutralizing antibodies against specific spike proteins, such as monoclonal antibody drugs that are currently widely used in the treatment of new coronaviruses, are designed based on this principle.

Finally, the interaction of the spike protein with the body's immune system is also evolving. The surface of the spike protein of some emerging viruses may constantly mutate, causing the antibodies produced by the human immune system to fail to recognize it, which is also a difficulty in the research of some virus vaccines. Therefore, in continuous exploration and research, we believe that we can find a better way to fight against the spike protein and further improve human immunity.

To sum up, the spike protein plays an important role between virus invasion and the human immune system. We need to pay attention to and study this area in depth to better protect human health. From this we can see the importance of immunity, Cistanche can significantly improve immunity because the polysaccharide components in Cistanche can regulate the immune response of the human immune system, improve the stress ability of immune cells, and enhance the bactericidal effect of immune cells.

Therefore, regular boosters are recommended especially for the high-risk population such as hemodialysis patients. 

Our previous study in the general population demonstrated superior humoral and cellular immunity against alpha, beta, and delta VOCs in convalescent and vaccinated patients as compared with vaccinated and noninfected individuals.2 

This study aimed to explore humoral and cellular wild-type–specific and Omicron BA.4/5–specific immunity in hemodialysis patients after COVID-19 mRNA vaccination by comparing vaccinated COVID-19 noninfected (Vþ C) to vaccinated COVID-19 convalescent (Vþ Cþ) hemodialysis patients.

To ensure that all patients had the same number of SARS-CoV-2 antigenic contacts, 22 noninfected hemodialysis patients who received 4 vaccinations of SARSCoV-2 mRNA (4 Vþ C) were compared with 7 patients with COVID-19 caused by Omicron BA.1/2 who received 3 vaccinations (3 Vþ Cþ) (Supplementary Table S1). 

We analyzed neutralizing antibodies against SARS-CoV-2 wild-type and Omicron BA.4/5 VOC by SARS-CoV-2 spike protein (S protein) pseudovirus assays. 

T-cell immunity reactive against SARS-CoV-2 wild-type and Omicron BA.4/5 overlapping peptide pools were analyzed by multiparameter flow cytometry (Supplementary Methods and Supplementary Figure S1).

In the vaccinated-only group (4 Vþ C), 21 of 22 patients (95.5%) showed a humoral immune response against SARS-CoV-2 wild-type, but only 8 of 22 patients (36.4%) against Omicron BA.4/5 VOC. In contrast, all 7 (100%) vaccinated and convalescent (3 Vþ Cþ) patients showed a humoral immune response against wild-type and 6 of 7 (85.7%) against BA.4/5. 

Although the incidence of patients with detectable wild-type–reactive and BA.4/5-reactive CD4 and CD8 T cells was similar in both groups (Figure 1a), the percentage of patients who had a combined humoral and cellular CD4 and CD8 T-cell response was significantly higher in the convalescent vaccinated group (62.5%) as compared with the vaccination-only group (25.0%) (Figure 1b). 

In line with it, the titer of neutralizing antibodies against Omicron BA.4/5 was significantly higher compared with vaccinated-only patients (Figure 1c). 

In contrast to the humoral immunity, there were no differences in the percentage of wild-type or Omicron BA.4/5– reactive CD4 and CD8 T cells and no significant differences in the production of proinflammatory cytokines interleukin-2 (IL-2) and tumor necrosis factor (TNF) by these cells between the 2 patient groups (Figure 1d–f).

The high incidence of humoral nonresponders against the current Omicron VOC indicates the urgent need for adjusted COVID-19 mRNA vaccination in this vulnerable population. 

A better humoral immunity observed in convalescent and vaccinated groups as compared with vaccinated-only patients can be explained by stronger antigenic stimuli, higher systemic inflammation, better antigenic stimulation, and immune cell recruitment during the natural infection as compared with vaccination.3

DISCLOSURE

All the authors declared no competing interests.

ACKNOWLEDGMENTS

We feel deep gratitude to the patients who donated their blood samples and clinical data for this project. 

We would like to acknowledge the expertise and technical assistance of the immune diagnostic laboratory (Sviatlana Kaliszczyk, Patrizia Wehler, Eva Kohut, Julia Kurek) of the Center for Translational Medicine at Marien Hospital Herne. This work was supported by grants from the Mercator Foundation and COVIDDataNet.NRW, and AIF/ZIM project EpiCov.

DATA AVAILABILITY STATEMENT

Data will be available upon request.

SUPPLEMENTARY MATERIAL

Supplementary Methods. 

Figure S1. 

Gating strategy. 

Table S1. 

Study population.

Reference

1. Garcia-Beltran WF, St Denis KJ, Hoelzemer A, et al. mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant. Cell. 2022;185:457–466.e4. 

2. Paniskaki K, Konik MJ, Anft M, et al. Superior humoral immunity in vaccinated SARS-CoV-2 convalescence as compared to SARS-COV-2 infection or vaccination. Front Immunol.

3. Babel N, Hugo C, Westhoff TH. Vaccination in patients with kidney failure: lessons from COVID-19. Nat Rev Nephrol. 2022;18:708–723.

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