Introduction
The individual immune response to SARS-CoV-2 defines the COVID-19 clinical evolution, ranging from asymptomatic to mild, moderate, or severe disease with possible multi-organ failure requiring intensive care support [
1].
Due to the severely impaired immune response to infection and immunization, patients with Primary Antibody Deficiencies (PAD) [
2] represent a potential at-risk group in the current COVID-19 pandemic [
3]. SARS-CoV-2 infected PAD patients have been reported [
4‐
6] with a clinical presentation varying from mild symptoms to death, with many asymptomatic patients also documented. We recently showed [
7] that Italian PAD patients showed a cumulative incidence and infection-fatality rate similar to the SARS-CoV-2 positive Italian general population. It is possible to consider that the low incidence might be related to the application of precautions measures our patients are used to following since PAD diagnosis. Although the infection rate and the infection-fatality rate were similar, the median age at death of PAD patients was lower compared to the general population, and most of these patients did not have predisposing comorbidities [
7]. A low or even absent antibody level is generating considerable anxiety in the PAD population aware of their incapacity to mount an adequate antibody response to infection and immunization [
8].
Vaccination is the safest and most effective tool to achieve a protective response in immunocompetent individuals in whom recent data demonstrated the high efficacy of SARS-CoV-2 immunization [
9,
10].
The European Society for Primary Immune Deficiency (ESID) recommends that PAD patients receive SARS-CoV-2 immunization provided that vaccines are based on killed/inactivated/viruses or on the use of mRNA [
11]. The rationale is, as for the influenza immunization, that immune responses may be generated despite a low or even absent antibody response [
12]. We are running a study with the aim to define the short- and long-term mechanisms of impaired or preserved immune responses to SARS-CoV-2 immunization in a population of adult PAD patients.
The immune response to vaccination occurs in the germinal centers where the mechanisms of somatic mutation and affinity-selection results in the generation of high-affinity memory B-cells (MBCs) and long-lived memory plasma cells that are indispensable elements of immunological memory and exert protection in case of infection [
13]. Other B-cell populations become transiently detectable in the peripheral blood. Atypical Memory B-cells (ATM) are mostly generated by extrafollicular reactions [
14] where antigen selection cannot occur. Plasmablasts (PBs) are short-lived antibody producing cells found in the blood early after vaccination. Most of them will die and only some will home to the bone marrow and develop into long-lived plasma cells [
15]. Thanks to the availability of fluorescent Spike protein, we have been able to determine the participation of the different cell types to the immune response in Healthy Donors (HD) and PAD patients.
We present here data on early immune responses after BNT162b2 immunization. In a cohort of immunized PAD patients, naive for SARS-CoV-2 infection or previously infected, we measured Spike-specific B- and T-cells and serum antibodies before immunization and one week after the second dose of the BNT162b2 vaccine. Results showed lack of antibody responses in the majority of patients with Common Variable Immune Deficiencies (CVID), and in all patients with X-linked Agammaglobulinemia (XLA). CVID patients generated atypical B-cell responses, as well as a variable response to the vaccination in terms of Spike-specific T-cells. XLA patients produced specific T-cell responses at the same extent of HD.
Discussion
Effective vaccines against SARS-CoV-2 are being administered worldwide with the aim of terminating the COVID-19 pandemic. As for all immunizations, the efficacy has been linked to the production of specific antibodies, which increase in response to all vaccines in use [
30,
31]. The majority of patients with PAD show clinical and immunological characteristics implicating a functional impairment of the B-cell compartment, and a dysregulation of T-cell responses causing hypo-gammaglobulinemia or agammaglobulinemia and susceptibility to a wide range of microbial infections [
32]. Despite the severely impaired antibody responses, when infected with SARS-CoV-2, one fourth of adult PAD patients remained asymptomatic and half of them showed a mild disease [
7]. It should be considered that a protective effect against severe COVID-19 could be due to the immune-modulatory effects on innate immunity exerted by immunoglobulin therapy also when administered at replacement dosages [
33]. However, data on immunogenicity of SARS-CoV-2 vaccine in patients with Inborn Errors of Immunity are few and limited to anecdotal cases or heterogeneous cohorts [
34]. After infection, a robust T-cells activity and humoral immunity against SARS-CoV-2 structural proteins in some patients with antibody deficiency has been described in five patients [
35]
. Consistent with the finding of a good antibody response after infection, also immunization with an mRNA COVID-19 vaccine resulted in high-level antibody titers in 11 patients with immune deficiency [
36] and in patients who were infected before immunization [
37].
Although the natural course of COVID-19 is primarily characterized by the function of the innate immune system, with a secondary involvement of T- and B-cells, vaccines are designed to force the adaptive immune system to generate neutralizing antibodies and memory B- and T-cells that effectively protect from COVID-19.
Here we showed that while HD produced specific antibodies and generated MBCs and activated MBCs with high binding capacity that significantly increased after immunization, these responses are lacking in all XLA and severely impaired in CVID patients after SARS-CoV-2 immunization, suggesting an incomplete response. Moreover, the few CVID patients who responded to immunization by anti-Spike IgG also developed ATMs and PBs with low binding capacity for Spike, instead of a response by MBCs. These responses are probably short-lived and should be reassessed over time. Interestingly, in one third of CVID patients vaccination induced B-cells specific for recombinant Spike protein inside the ATM population, possibly suggesting that the B-cell responses occurred mostly at extra-follicular sites [
38], as recently demonstrated [
39]. In line with this hypothesis, RBD + B-cells were undetectable in CVID patients, whereas RBD + B-cells represent 20% of the specific anti-Spike response in HD (unpublished data) able to develop and successfully terminate the germinal center reaction [
40]. Thus, CVID patients were able to respond to immunization by two doses of BNT162b2 with atypical lineage B-cells induced by a primary exposure to a novel antigen. It has been suggested that atypical B-cells are short-lived activated cells, in the process of differentiating into plasma cells [
26,
41]. In addition, interesting information was gained by the parallel study of the T-cell responses, showing a robust generation of Spike-specific T-cells in all but one patient with XLA, and in HD. Specific-T-cell responses were induced in a minority of CVID patients with a variable frequency. Based on data on response to influenza virus immunization [
11], we expected a more efficient generation of specific T-cells. However, this was not the case. While after influenza virus immunization T-cells are generated after multiple exposures to viral antigen following infection and immunization, SARS-CoV-2 is a pathogen never encountered before, since SARS-CoV-2 Spike and the RBD domains are district from the S proteins of most members of the family of coronavirus [
42]. Then, it is possible that the first antigenic stimulation was not sufficient to induce an early T-cell response.
Based on these data, how can we explain the paucity of symptoms or the mild COVID-19 course in PAD patients, and what might we expect after immunization?
To pathogens for which there is no preexisting immunity, our organism reacts by rapidly engaging the innate immune system with the intent to limit the infection. The adaptive immune response develops slowly and needs two weeks to generate the most specific and effective defensive tools. However, the vast majority of PAD patients infected with SARS-CoV-2 did not show signs of hyper-activation of the innate immunity [
3‐
5]. This could possibly be due to the immunomodulatory effects on innate immune cells of replacement with polyvalent immunoglobulins [
33], and to a poor adaptive immunity response. This pattern of immune responses resembles what we have already shown in asymptomatic immunocompetent subjects [
43], and further demonstrated that a balanced cytokine production resulting from a functional but not hyper-reactive innate immunity and a poor adaptive immunity are the conditions associated with an early benign COVID-19 course. Our data are partially in contrast to observations reported in small cohorts of PAD, showing that the majority of CVID patients are able to respond to the BNT162b2 vaccine [
34]. Differently from previous studies, we described a homogeneous cohort of patients, separately analyzing CVID and XLA at different time points.
In summary, a minority of PAD patients showed adaptive, atypical immune responses after SARS-CoV-2 immunization. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown, since we do not know the levels of antibodies or the frequency of specific B- and T-cells required to protect from the infection.
It should be remembered here that each PAD patient should be studied as unique in terms of cellular and humoral responses due to the variability of their underlying immune deficiency. In our series, antibody response after two doses of BNT162b2 immunization—overlapping that of HD—was found in one patient homozygous for TNFRSF13B mutation, but not in two patients with a heterozygous TNFRSF13B mutation. In a previous study, we demonstrated that CVID patients with biallelic TNFRSF13B mutations responded also to polysaccharide vaccines, while CVID with only one TNFRSF13B mutation showed an impaired response to vaccination [
44].
A major limitation of our study is the short time of observation after vaccination. We do not know if the antibody and cellular responses might persist or decline over time, nor if PAD patients might show delayed responses. However, we do not expect to observe major changes in the immune response to SARS-CoV-2 with time after immunization. Is it possible to hypothesize a boost of specific B-cell immunity? In those CVID patients who were previously infected with SARS-CoV-2, IgG were detectable when they received two vaccine doses administered at least three months after SARS-CoV-2 infection recovery, suggesting that if IgG were produced, they might persist after the primary infection. Moreover, in these previously infected CVID patients, IgG response was boosted by the subsequent immunization. After immunization, anti-Spike IgG were higher than in patients who were not previously infected, showing that SARS-CoV-2 infection more effectively primed the immune response than the vaccine alone. Whether it may be useful to administer a third vaccine dose to CVID patients not previously infected, should be demonstrated as suggested for patients with solid organ transplantation undergoing immunosuppressive treatment [
45].
Moreover, data available from T-cell immunity after influenza virus vaccination in PAD [
11] might suggest a possible strategy aimed to boost also the SARS-CoV-2 T-cell specific responses by additional vaccine doses.
Since antibody titers are not a precise indicator of the magnitude of memory cells [
46] our strategy is to follow-up our cohort by serological and cellular investigations. The only epidemiological observation we have for now is that one CVID patient experienced an infection by SARS-CoV-2 three months after completing the two doses vaccination. He remained asymptomatic possibly due to the prompt administration of monoclonal antibodies [
47]. For now, SARS-CoV-2 positive CVID patients might benefit from these new treatments. Prevention of infection may be achieved by the presence of SARS-CoV-2 antibodies in the coming lots of gamma globulins, regularly used to substitute the missing or partial response to infections and vaccination.
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