Clinical and immunological outcomes of SARS-CoV-2 infection in patients with inborn errors of immunity receiving different brands and doses of COVID-19 vaccines

ABSTRACT Clinical and immunological outcomes of SARS-CoV-2 infection in patients with inborn errors of immunity receiving different brands and doses of COVID-19 vaccines Introduction Vaccines against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) provide successful control of the coronavirus-2019 (COVID-19) pandemic. The safety and immunogenicity studies are encouraging in patients with inborn errors of immunity (IEI); however, data about mortality outcomes and severe disease after vaccination still need to be fully addressed. Therefore, we aimed to determine the clinical and immunological outcomes of SARS-CoV-2 infection in patients with IEI who have received vaccination. Materials and Methods Eighty-eight patients with a broad range of molecular etiologies were studied; 45 experienced SARS-CoV-2 infection. Infection outcomes were analyzed in terms of genetic etiology, background clinical characteristics, and immunization history, including the type and number of doses received and the time elapsed since vaccination. In addition, anti-SARS-CoV-2 antibodies were quantified using electrochemiluminescent immunoassay. Results Patients were immunized using one of the three regimens: inactivated (Sinovac, Coronavac®), mRNA (BNT162b2, Comirnaty®, Pfizer-Biontech), and a combination. All three regimens induced comparable anti-SARS-CoV-2 IgG levels, with no differences in the adverse events. Among 45 patients with COVID-19, 26 received a full course of vaccination, while 19 were vaccine-naive or received incomplete dosing. No patients died due to COVID-19 infection. The fully immunized group had a lower hospitalization rate (23% vs. 31.5%) and a shorter symptomatic phase than the others. Among the fully vaccinated patients, serum IgM and E levels were significantly lower in hospitalized patients than non-hospitalized patients. Conclusion COVID-19 vaccines were well-tolerated by the IEI patients, and a full course of immunization was associated with lower hospitalization rates and a shorter duration of COVID-19 symptoms.

The impact of SARS-CoV-2 on immunologic response is yet to be fully understood (9)(10)(11).Unlike other viruses, SARS-CoV-2 can escape from the innate immune system during the asymptomatic phase (11).It is known that anti-interferon antibodies contribute to disease severity (12).Complement system responses exacerbate COVID-19, and natural killer (NK) cell responses are compromised during the infection (13).The adaptive immune system is also disturbed, and persistent lymphopenia is a poor prognostic marker of severe disease.Despite the production of antibodies against SARS-CoV-2, it has been observed that in many deceased COVID-19 patients, the presence of antibodies was inadequate to provide protection against severe illness and failed to effectively neutralize the virus (14).Furthermore, effective early-T cell responses are associated with milder disease, and exaggerated or inadequate T-cell responses may lead to poor outcomes (15)(16)(17)(18)(19).
Patients with inborn errors of immunity (IEI) may exhibit heightened susceptibility to more severe COVID-19 infections.However, the specific subtypes COVID-19, 26 received a full course of vaccination, while 19 were vaccine-naive or received incomplete dosing.No patients died due to COVID-19 infection.The fully immunized group had a lower hospitalization rate (23% vs. 31.5%)and a shorter symptomatic phase than the others.Among the fully vaccinated patients, serum IgM and E levels were significantly lower in hospitalized patients than non-hospitalized patients.  of IEI play a crucial role in shaping the course of the disease (8,20), which makes it challenging to provide overarching recommendations for this particular population.It is well-known that patients with common variable immunodeficiency (COVID-19) can experience severe infection requiring intensive care; however, there are inconsistent results among patients (21)(22)(23)(24).

Conclusion
Vaccination against COVID-19 is the mainstay of protecting from severe disease and terminating the COVID-19 pandemic.The effectiveness of vaccines in preventing disease following exposure to SARS-CoV-2 ranges from 50% to over 90%.However, the efficacy in preventing severe disease has been demonstrated to be nearly 95% (25,26).In our country, two vaccines are currently available for use: a recently introduced mRNA vaccine (BNT162b2, Comirnaty ® , Pfizer-BioNTech) and an inactivated vaccine (Sinovac, CoronaVac ® , Vero-cell) (27).Vaccination against SARS-CoV-2 has been endorsed by healthcare experts and has been demonstrated to be both safe and effective for individuals with IEI, who are also being prioritized globally (28,29).However, most data about the efficacy and safety of the vaccines are gathered from trials performed on healthy individuals.Limited data are available concerning the immunogenicity of SARS-CoV-2 vaccines and the subsequent outcomes of COVID-19 infection among vaccinated individuals with IEI.Due to the underlying immunological deficiencies, patients with IEI typically exhibit reduced or even absent vaccine responses (30).While some recent studies have indicated favorable tolerance and immunogenicity, further research is necessary to provide a comprehensive understanding (31)(32)(33).
Studies investigating the immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with IEI have shown diminished levels of SARS-CoV-2 specific IgG and T-cell responses in comparison to the general healthy population (30-75% and 50-70% versus 95-100%).Additionally, patients exhibited lower titers of SARS-CoV-2 specific IgG, reduced efficacy in virus neutralization, and decreased magnitude of T-cell responses when compared to healthy donors.Notably, patients with low serum IgG, IgA levels, and those of older age demonstrated poorer vaccine responses (34).
In this study, our objective was to assess the clinical outcomes of SARS-CoV-2 infection in patients with IEI who have completed the full course of vaccinations, and to compare these outcomes with those of vaccine-naive and/or incompletely vaccinated patients.In addition, our study also assessed the efficacy and seroconversion rate of different vaccine regimens in patients with IEI.(35)(36)(37).Vaccination status was defined as full course vaccination (two or more doses) and incomplete vaccination (vaccine-naive or one dose of immunization).Probable COVID-19 variants were determined according to COVID-19 infection time which was in widespread global circulation at the time stated by World Health Organization (WHO).The severity of SARS-CoV-2 infection was defined using criteria according to WHO interim COVID-19 guidelines.

Patients
We collected a comprehensive dataset encompassing demographics, detailed clinical features with baseline therapies [prophylactic antibiotic usage, IgG replacement therapy (IgRT), immunosuppressive drugs], and immunological parameters (serum-IgG concentrations, lymphocytes enumeration and subsets, vaccination status, and infection time of SARS-CoV-2 and other laboratory assessment).SARS-CoV-2 infection was diagnosed by positive reverse transcription polymerase chain reaction (RT-PCR).
Data on COVID-19 infection was collected using a structured questionnaire, including contact history and COVID-19-related symptoms.Patients were also reviewed for the duration of hospitalization, treatment regimens during hospitalization or at home, and outcomes of COVID-19 infection.
Blood samples for anti-SARS-CoV-2 antibodies were collected before the subsequent dose of intravenous IgRT and at any time in patients who received subcutaneous IgRT (SCIG).An anti-SARS-CoV-2 S assay kit (Elecsys ® Anti-SARS-CoV-2 S kit, Roche Diagnostic, USA) was used to detect antibodies.This is an electrochemiluminescent immunoassay for detecting antibodies to SARS-CoV-2 nucleocapsid (N) protein and performed on the Cobas ® e401 analyzer.The antigens within the reagent capture predominantly anti-SARS-CoV-2 specific-IgG but also anti-SARS-CoV-2 specific-IgA and IgM.Serum samples were tested in accordance with the manufacturer's instructions and results greater than 0.8 U/mL were categorized as seropositive.We assessed the antibody responses at 1/10 of diluted serum samples.
The study protocol was approved by the local ethics committee of our hospital with decision number 210.All participants provided written informed consent.

RESULTS
A total of 88 IEI patients were enrolled in this study.Among our IEI cohort, 45 patients (51.1%) had encountered SARS-CoV-2 infection, and no deaths occurred.The study design is shown in Figure 1.The median age of participants was 35 years (IQR= 25.5-40), and 53.3% were male.Patients' demographic characteristics, vaccination status, diagnosis of IEI, hospitalization, and other features are summarized in Table 1.
The median interval between the day of the last vaccination and SARS-CoV-2 infection was 85 days (IQR= 28.5-161.25),and the majority of patients received at least two doses of vaccination during exposure to SARS-CoV-2 (Figure 2A).The median time interval between the day of the final vaccine dose and the sampling of anti-SARS-CoV-2 antibodies was 133 days (IQR= 79-229).The median time interval between the day of SARS-CoV-2 infection and the testing for anti-SARS-CoV-2 antibodies was 140.5 days (interquartile range= 62.7-347.7).
The overall seroconversion rate among the study group after SARS-CoV-2 infection was 93% (n= 42).Seronegativity was observed in cases of BTK deficiency (n= 1) and immune dysregulation without a genetic etiology (n= 2).Interestingly, all seronegative patients were on IgRT.There was no significant difference in the levels of anti-SARS-CoV-2 antibodies among patients who received mRNA, inactivated vaccines, or combinations of vaccines (Figure 2B).Due to the regular usage of IgRT, vaccine-naive patients showed similar titers of anti-SARS-CoV-2 antibodies compared to the fully vaccinated patients (Table 2).Also, a slightly positive correlation between IgA and titers of anti-SARS-CoV-2 antibodies was detected (r= 0.3561, p= 0.021).It is worth mentioning that the hospitalization rate was higher among vaccine-naive or incompletely vaccinated patients (31.5%, 6/19) in comparison to fully vaccinated patients (23%, 6/26), underscoring the significance of vaccination within this vulnerable population (Table 2).There was no mortality after immunization, while the dominant spreading variants were delta and omicron mainly caused the infection observed during the study period (Figure 3).No statistically significant differences were observed between fully vaccinated individuals and those who were incompletely vaccinated or vaccine-naive, in terms of the duration required for SARS-CoV-2 PCR results to become negative and the number of days with COVID-19 symptoms (Figure 4A, B).IgE levels were significantly lower than in nonhospitalized patients (Table 3).The median duration of hospitalization in fully vaccinated patients was 4.5 (IQR= 2.75-6.5).The median duration of symptomatic days in hospitalized patients was 17.5 (IQR= 9.75-27) and significantly higher than in non-hospitalized patients (p= 0.012), while the median time to negative PCR test results after infection was similar in hospitalized and non-hospitalized patients.In addition, the median titer of anti-SARS-CoV-2 antibodies in hospitalized patients was dramatically lower than in non-hospitalized patients (p= 0.016).

Among fully vaccinated patients requiring hospitalization for SARS-CoV-2 infection, IgM and
Finally, when we compared hospitalized and nonhospitalized patients regardless of vaccine status (fully vaccinated, incomplete regimens, and vaccinenaive), higher serum immunoglobulin levels and lower symptomatic days were observed in nonhospitalized patients (Table 4).

DISCUSSION
In this report, we present the efficacy and immunogenicity of various brands of SARS-CoV-2 vaccines, as well as the outcomes of COVID-19 vaccine breakthrough cases in different groups of patients with IEI.Our study evaluated different types of IEI patients who encountered COVID-19 infection; 19 were vaccine-naive or incompletely vaccinated, and 26 were fully vaccinated.No deaths attributed to COVID-19 infection were recorded.Nevertheless, the rate of hospitalization was higher among individuals who were incompletely vaccinated or vaccine-naive, in comparison to the fully vaccinated group.

The case fatality rate in the unvaccinated period
Research about the case fatality rate and the intensive care unit (ICU) admission rate due to COVID-19 infection in IEI patients showed a higher rate compared to similar ages of the general population.
In a recently published study, which represented the largest review of its kind involving 649 patients with IEI, the rates of ICU admission and case fatality rate (CFR) following COVID-19 infection were identified as 16% and 9%, respectively (38).While in the general population, the CFR is 2.1% and increases with older ages [(range 0.5-18%), 0.3% <40 years to 13-20% in >80 years] (39,40).However, in Giorgia et al.'s study, the CFR was higher among IEI patients when evaluated for similar age ranges (7% for 20-40 years up to 36% for >70 years) (38).Our previous study also confirmed this result, which showed the CFR as 34% (8).In our current study, there was no mortality after vaccination, and the mortality rate before vaccination was higher in IEI patients when compared with the general population.The mortality was unrelated to the dominant spreading variant observed during the study period.
It was shown that higher IgM levels and greater numbers of CD19 + B cells were reported in seropositive patients.Also, both IgA and IgM levels were positively correlated with the magnitude of the antibody response following vaccination (44).
According to our study, the median IgA, IgM, IgG, and IgE levels were significantly lower in hospitalized IEI patients than in non-hospitalized ones, regardless of the vaccination.Likewise, our study reported a significant positive correlation between IgA and titers of anti-SARS-CoV-2 antibodies.These results delineate that patients with high immunoglobulin levels can display better outcomes after COVID-19 infection.

The severity of COVID-19 infection
The clinical spectrum of COVID-19 in COVID-19 patients varies from asymptomatic to mild symptoms to death, which could be related to the heterogenicity of IEI-studied groups (24,(45)(46)(47)(48)(49)(50).An Italian study conducted among patients with COVID-19 revealed that the case fatality rate (CFR) and cumulative incidence rate were comparable to those observed in the general population (51).However, in contrast to the general population, COVID-19-related deaths among COVID-19 patients have occurred at a lower median age (23,52,53).Similarly, in another cohort of COVID-19 patients, about 65% had a mild and asymptomatic COVID-19 infection severity (54).On the other hand, a cohort of IEI found that unvaccinated patients showed a higher hospitalization rate when  In our study, severe COVID-19 disease was seen in 24.5% of the IEI patients, and the hospitalization rate for fully vaccinated patients was 23% and 31.5% for vaccine naive/incompletely vaccinated patients, respectively.After vaccination, there was a notable decrease in the hospitalization rate, which aligns with findings from other studies.

Boosting Vaccination and Treatment Recommendations for Individuals with IEI and COVID-19 Infection
The immunogenicity of two or more vaccine doses in patients with heterogeneous IEI remains unclear, and we have limited data on booster SARS-CoV-2 vaccination.A study was conducted with 33 adults and children with IEI, 16 vaccinated with the Pfizer/ Biontech BNT162b2 and 17 with Coronavac receiving two or three vaccine doses.The seropositivity rates were 55% after the second dose and 74% after the third dose.As a result, they advised administering three vaccine doses to individuals with IEI in order to ensure optimal immunogenicity (56).A similar pattern was noted in another study, where sequential administration of up to three doses resulted in an elevation of protective antibody levels from 20.2 AU/mL to 145 AU/mL after the third dose (57).Their findings are in line with recent studies, demonstrating an increase of anti-SARS-CoV-2 antibodies in most patients with humoral immunodeficiencies (31)(32)(33)42,(58)(59)(60)(61).In our study, a substantial level of anti-SARS-CoV-2 antibodies reaching up to 2500 U/mL was identified, potentially attributable to the administration of two or more vaccine doses, further augmented by a SARS-CoV-2 infection.
The current COVID-19 vaccine guidelines for patients with PID include administering three initial doses of mRNA vaccine, followed by a booster dose, and subsequently a second booster dose four months after the last booster doses (62).
IgG products currently exhibit elevated anti-SARS-CoV-2 antibody titers when compared to earlier trials, owing to the broader vaccine coverage that has generated higher antibody levels than the infection itself in the general population, encompassing plasma donors as well (63).Furthermore, noteworthy

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COVID-19 vaccines were well-tolerated by the IEI patients, and a full course of immunization was associated with lower hospitalization rates and a shorter duration of COVID-19 symptoms.Key words: Inborn errors of immunity; the Pfizer/BioNTech BNT162b2; Sinovac; SARS-CoV-2; COVID-19 vaccines ÖZ İmmün sistemin doğuştan gelen kusurları olan hastalarda farklı marka ve dozlarda uygulanan SARS-CoV-2 aşısı sonrası SARS-CoV-2 enfeksiyonunun klinik ve immünolojik sonuçları Giriş: Şiddetli akut solunum sendromu koronavirüs- Median and interquartile range (IQR) values for continuous variables and the frequency and percentage for the categorical variables were calculated.Differences between ordinal data were evaluated with the Mann-Whitney U test and the Kruskal-Wallis test.Categorical variables were evaluated with the two tailed Chi-square or Fisher's exact tests.Correlation tests were assessed with the Spearman's correlation test.Statistical analyses were done using IBM SPSS 25 (SPSS Inc, Chicago, III) and GraphPad Prism 8 (GraphPad Software Inc.San Diego, California, USA).Differences in values were considered significant at a p-value of <0.05.

Figure 1 .
Figure 1.The study design and enrolled IEI patients.

Table 3 .
Clinical and immunological characteristics of fully-vaccinated patients with hospitalization versus non-hospitalization PAD: Predominantly antibody deficiency, ID: Immune dysregulation disorders, CID: Combined immunodeficiencies.

Table 4 .
Correlation between clinical parameters and ultrasound measurements

Interval between COVID-19 infection and sampling antibody (days, median, IQR)
: Predominantly antibody deficiency, ID: Immune dysregulation disorders, CID: Combined immunodeficiencies.seropositivitywas observed in an XLA patient who was both COVID-19 naive and unvaccinated, likely attributed to the transmission of SARS-CoV-2 specific IgG from IgG products.The National Institutes of Health treatment guidelines panel recommends the use of antiviral paxlovid and remdesivir for patients with PID who have moderate or severe COVID-19 infections.In Türkiye, the Minister of Health recommends remdesivir for patients with immunodeficiency.Nevertheless, in our study, only two patients received at-home therapy with remdesivir.This study had certain limitations.Firstly, the absence of a healthy control group was a limitation; however, our findings aligned with existing research.Another constraint was the relatively small number of cases, although the inclusion of a diverse and rare disease group may justify the sample size.Additionally, T-cell response testing, considered a marker of viral neutralization, was not conducted.Nevertheless, the study provides insights into the efficacy and safety of various vaccine brands in patients with IEI.Furthermore, clear positive clinical outcomes were evident among these vulnerable patients following SARS-CoV-2 infection post-vaccination. PAD