Immunogenicity and clinical outcomes of booster mRNA vaccine BNT162b2 in primary antibody deficiencies

doi:10.21203/rs.3.rs-3307104/v1

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Immunogenicity and clinical outcomes of booster mRNA vaccine BNT162b2 in primary antibody deficiencies

https://doi.org/10.21203/rs.3.rs-3307104/v1

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Purpose:Anti-SARS-CoV-2 mRNA vaccines may elicit humoral responses in patients with primary antibody deficiency. However, this response is limited by its rapid waning and low levels of virus-neutralizing antibodies. There is limited evidence for the efficacy of the booster vaccination in patients with primary antibody deficiencies.

Methods:This prospective observational cohort study focused on the clinical outcomes (proportion of infected patients, disease severity, and adverse event incidence) and dynamics of humoral immune responses (specific post-vaccination and virus-neutralizing antibodies) after booster (third) mRNA anti-SARS-CoV-2 vaccine in patients with common variable immunodeficiency (CVID). The patients were followed-up for seven months.

Results:Eighteen participants were enrolled from 21 screened patients with CVID. One month after the booster vaccination, the proportion of responders increased from 16.7%, and the mean concentration of anti-SARS-CoV-2 RBD antibodies increased from 13.95 U/mL to 72.2% and 302.6 U/mL, which was significantly lower compared to healthy donors (mean 1949 U/ml). Patients with CVID also had reduced titers of virus-neutralizing antibodies. Notably, response rate and mean specific antibody concentrations increased within the follow-up period up to 100% and 1346 U/mL, respectively, at month seven. These results may be confounded by the passivetransmission of specific antibodies. Local reactions were the most common adverse events. No severe adverse events were reported.

Conclusion:Booster vaccination and passively transmitted anti-SARS-CoV-2 specific antibodies from immunoglobulin replacement therapy result in high serum levels of specific antibodies. However, this is limited by lower titers of neutralizing antibodies and different immunogenicity against viral variants. Administration of a booster dose of the BNT162b2 vaccine was safe; no new safety concerns were raised.

Primary antibody deficiency

Common variable immunodeficiency

SARS-CoV-2

COVID-19

mRNA vaccine

booster vaccination

immunogenicity

humoral response

Since the SARS-CoV-2 outbreak in 2019, COVID-19 has affected 767 million individuals and led to seven million deaths [1]. Higher age, male sex, obesity, malignancy, chronic pulmonary, cardiovascular, and renal diseases were identified as the primary risk factors for poor COVID-19 outcomes [2, 3]; however, disease severity depends on the virus variant. The Omicron variant showed significantly reduced mortality and severity compared with the Delta variant [4, 5]. COVID-19 significantly impacted patients with inborn errors of immunity (IEI), particularly those with common variable immunodeficiencies in whom a greater risk of mortality and hospital admissions has been reported [6–8]. Comorbidities have been identified as a primary factor that contributes to disease severity [9].

CVID is one of the most frequent primary antibody deficiency (PAD) and is characterized by impaired immunoglobulin and specific antibody production, immune system dysregulation, and variable clinical manifestations, including recurrent respiratory tract infections and a broad spectrum of non-infectious complications [10, 11]. Noninfectious manifestations may affect over two-thirds of all patients with CVID, including chronic lung disease, lymphoproliferation, autoimmunity, enteropathy, and malignancy, with significant overlap with COVID-19 severity-associated risk factors[12, 13]. Thus, patients with CVID belong to a high-risk population in whom the prevention of SARS-CoV-2 is crucial.

Despite the short-term efficacy of preventive measures, such as social distancing, mask-wearing, and handwashing [14], they failed from a long-term perspective [15, 16]. In contrast, vaccination against SARS-CoV-2 has been effective and safe for preventing severe COVID-19 in the general population [17]. However, long-term efficacy may be influenced by the waning of the immune response [18] and variable immune responses against different viral strains [19, 20]. Therefore, booster vaccination and administering adapted vaccines are needed to maintain a sufficient level of protection[21, 22]. Limited responses to vaccination and rapid waning have also been reported in patients with CVID [23–25]. Therefore, determining the immunogenicity, safety, and efficacy of booster vaccinations in patients with IEI is crucial. Therefore, we conducted a study focused on the immunogenicity, safety, and clinical outcomes following the third (booster) mRNA vaccine, Comirnaty (BNT162b2).

Ethics statement

This study was approved by the Ethics Committee of Motol University Hospital (no. EK-753.1.3/21, issued June 10, 2020) and conducted in accordance with the guidelines of the Declaration of Helsinki. Informed consent was obtained from all patients before enrollment.

Study design

In the present study, we report the results of a prospective observational study focusing on the immunogenicity, safety, and clinical outcomes of a booster (third dose) of the monovalent mRNA vaccine, BNT162b2 (Comirnaty; BioNTech Manufacturing GmbH, Mainz, Germany). This study followed the Strengthening the Reporting of Observational Studies in Epidemiology recommendations [26]. Patients received one standard dose (0.3 mL/30 µg of mRNA) intramuscularly after a six month interval after completing the primary vaccination schedule. The follow-up period was divided into five consecutive visits: screening, CVID and healthy donor (HD) recruitment, inclusion/exclusion criteria assessment, clinical data collection, visit one (baseline)–vaccine administration (day 0), visit two–month one (day 30 +/-3), visit three–month four (day 120 +/-7), and visit four–month seven (day 210 +/-7). The study design is illustrated in Fig. 1. This study was conducted between November 2021 and June 2022.

Study population

This study included adult patients with CVID who met the European Society for Immunodeficiency/International Consensus Document diagnostic criteria [10, 11].

Administration of the booster (third) vaccine was indicated by the attending immunologist and performed at a specialized vaccination center. Patients with COVID-19 in the previous 90 d, acute infection, acute severe noninfectious complications, or other contraindications for vaccination were excluded. Their results were compared with those of 12 sex- and age-matched HDs.

Humoral response assessment

The primary goal of this study was to determine humoral responses after the administration of the booster (third) mRNA vaccine, BNT162b2, in patients with CVID. Responders were defined as individuals in whom anti-RBD SARS-CoV-2 specific antibodies exceeded the positive cutoff level (≥ 22 U/mL) at month one. Specific antibodies were detected using a chemiluminescence assay (KleeYa, Diatron, Budapest, Hungary).

We assessed the neutralizing properties of these antibodies. The virus neutralization test (VNT) was performed according to a previously published protocol [27] using SARS-CoV-2 strains derived from clinical samples: Delta 128940/21 and Omicron 55174/22. Virus stock suspensions were prepared by amplification on the CV-1 cell line (African green monkey kidney fibroblasts). Serum samples were diluted to final concentrations of 1/10-/2560. Uninfected cells were stained with a neutral red dye. The VNT results were expressed as a virus-neutralization titer, representing an inverted value of the highest sample dilution neutralizing the cytopathic effect of the virus by > 50%. Positivity was determined using a titer ≥ 20.

The presence of Anti-RBD SARS-CoV-2 specific antibody was also tested in 10 different batches of immunoglobulin replacement therapy (IRT) solutions with an expiration period from September 2023 to December 2024, used for immunoglobulin substitution in the enrolled patients. All solutions were diluted with a 5% bovine serum albumin (lyophilized IgG-free powder, Merck KGaA, Darmstadt, Germany) solution to a concentration of 1%, corresponding to the IgG concentration in human plasma.

Clinical outcomes

The incidence of adverse events, infection ratio, and COVID-19 severity were measured as the primary clinical outcomes. Adverse events (AEs) were reported using a patient clinical questionnaire, focusing on local (injection-site reactions) and systemic (fever, headache, myalgia, and arthralgia) reactions and emergency medication (e.g., analgesic/antipyretic drugs). Pain intensity and overall AE severity were self-reported by patients on 10-point and 100-point visual analog scales. Severe AEs were defined as acute conditions requiring hospital admission or urgent medical intervention followed by vaccination.

The infection ratio was determined as the proportion of patients with CVID in whom SARS-CoV-2 infection was confirmed using reverse transcription-polymerase chain reaction (RT-PCR). Testing was indicated in cases where respiratory tract infection symptoms were present or following risky contact with a SARS-CoV-2-positive individual. COVID-19 disease severity in RT-PCR-positive patients with CVID was divided into five groups according to severity definitions from the World Health Organization [28]: asymptomatic, mild (mild fever, cough, no viral pneumonia), moderate (fever, viral pneumonia, hospital admission without oxygen therapy), severe (viral pneumonia, signs of respiratory distress: SpO2 ≤ 93%, tachypnea > 30 respiratory rate, non-invasive ventilation), and critical (acute respiratory distress syndrome).

Statistical analysis

The mean and 95% confidence intervals (95% CI) were calculated for continuous data (age, disease duration, immunoglobulin dose, and laboratory parameters). Statistically significant differences in the means were assessed using the Mann–Whitney and Wilcoxon tests for non-normally distributed unpaired and paired data, respectively. Normality was tested using the Shapiro–Wilk normality test. Proportions were calculated for attributive data, and statistically significant differences in proportions were evaluated using Fisher’s exact test. Statistical significance was set at p < 0.05. Statistical analyses were performed using GraphPad Prism 8 software (GraphPad Software; San Diego, CA, USA).

Baseline characteristics of the cohort

From a cohort of 21 patients with CVID who were vaccinated according to the primary vaccination scheme six months prior and screened for the extended study following the effect of the booster (third) BNT162b2 vaccine, 18 patients were included based on the inclusion and exclusion criteria. In total, three screened patients were excluded because of COVID-19 infection in the previous 90 d. At baseline, six males (33.3%) and twelve (66.7%) females were enrolled. The mean age was 49.9 y (95% CI: 43.89–56.0), and the disease duration was 11.28 y (95% CI: 7.5–15.06). All patients were on IRT; four (22.2%) received intravenous immunoglobulin therapy, and eleven subcutaneous IRT (77.8%). The mean dose of IRT was 327.6 mg/kg/month (95% CI: 278.5–376.7), and the IgG trough levels were 6.64 g/L (95% CI: 5.7–7.6). In addition, three patients (16.7%) required antibiotic prophylaxis. Noninfectious complications were observed in 14 patients (77.8%). The most frequent non-infectious manifestations were splenomegaly and/or lymphadenopathy (44.4%, n = 8/18), bronchial asthma (38.9%, n = 7/18), chronic lung disease (27.8%, n = 5/18), enteropathy (27.8%, n = 5/18), and hepatopathy (16.7%, n = 3/18). Three of these patients (16.7%) were treated with immunosuppressants at the time of vaccination, including glucocorticosteroids (two patients) and sulfasalazine (one patient). The baseline characteristics are summarized in Table 1.

Table 1

Baseline characteristics of enrolled patients, statistically significant difference (p < 0.05) marked in bold. no., number; yrs., years; pts., patients; CI, confidence interval; IRT, immunoglobulin replacement therapy; Ig, immunoglobulin; ATB, antibiotics
Characteristics	All (n = 18)	Responders (n = 11)	Non-responders (n = 7)	p- value
DEMOGRAPHY
Sex (no. of females, %)	12 (67%)	8 (73%)	4 (57%)	0.627
Age (yrs., 95%CI)	49.9 (43.9–56.0)	44.4 (38.2–50.5)	58.7 (48.0-69.4)	0.017
DISEASE CHARACTERISTICS
Disease duration (yrs, 95%CI)	11.3 (7.5–15.1)	10.0 (4.8–15.2)	13.3 (6.3–20.2)	0.292
Non-infectious complications (nr. of pts., %)	14 (78%)	8 (73%)	6 (86%)	0.99
TREATMENT CHARACTERISTICS
IRT dose (mg/kg/month, 95%CI)	327.6 (278.5-376.7)	299 (251.6-346.4)	368.6 (257.5-479.6)	0.28
ATB prophylaxis (no. of pts, %)	3 (17%)	1 (9%)	2 (29%)	0.528
Baseline immunosuppression (no. of pts., %)	3 (17%)	1 (9%)	2 (29%)	0.528
LABORATORY PARAMETERS
Serum IgG (trough g/L, 95%CI)	6.64 (5.7–7.6)	6.36 (4.9–7.8)	7.0 (5.4–8.5)	0.607
Serum IgA (g/L, 95%CI)	0.11 (0.06–0.16)	0.12 (0.04–0.19)	0.1 (0.03–0.17)	0.58
Serum IgM (g/L, 95%CI)	0.21 (0.1–0.31)	0.21 (0.08–0.34)	0.19 (0.0-0.4)	0.376
Lymphocytes (abs, E10/9)	1.39 (1.06–1.71)	1.31 (1.03–1.59)	1.44 (0.69–2.2)	0.84
CD3 cells (abs, E10/9)	1.05 (0.82–1.27)	0.98 (0.72–1.24)	1.15 (0.63–1.67)	0.437
CD4 cells (abs, E10/9)	0.55 (0.45–0.66)	0.55 (0.44–0.67)	0.56 (0.31–0.81)	0.947
CD8 cells (abs, E10/9)	0.43 (0.29–0.57)	0.36 (0.2–0.52)	0.54 (0.25–0.83)	0.246
CD19 cells (abs, E10/9)	0.15 (0.09–0.22)	0.16 (1.0-0.21)	0.15 (0.0-0.33)	0.46

Humoral response

Before the administration of the booster (third) mRNA vaccine, Comirnaty (six months after the completion of the primary vaccination scheme), the response persisted in 16.7% of patients (n = 3/18). The mean serum concentration of anti-RBD SARS-CoV-2-specific antibodies was 13.95 U/mL (95% CI: 6.63–21.27). One month after booster vaccination, the proportion of responders increased to 72.2% (n = 13/18), and the mean concentration of specific antibodies increased to 302.6 U/mL (95% CI: 91.7–513.5). However, the response was significantly lower than that of HDs (1949 U/mL, 95% CI: 1643–2256, p < 0.0001), in whom virus-specific antibodies were detected (n = 12/12) (Fig. 2). We also found significantly lower titers of virus-specific neutralizing antibodies against Delta (mean titer: 37.86, 95% CI: 5.26–70.5 vs. mean titer: 986.7, 95% CI: 219.8–1753, p < 0.0001) and Omicron variants (mean titer: 11.43, 95% CI: 0.0–24.8 vs. mean titer: 204, 95% CI: 35.3–372.7, p < 0.0002) (Fig. 3). This response was affected by increasing age. The responders were significantly (p = 0.017) younger compared to non-responders: 44.4 (95% CI: 38.2–50.5) vs. 58.7 y (95% CI: 48.0–69.4).

Notably, the serum concentration of virus-specific antibodies and the proportion of responders continuously increased during the follow-up period. At month four, a response was detected in 68.8% (n = 11/16) of the patients, and the number of responders further increased to 100% (15/15). The mean serum levels of specific antibodies were 1036 U/mL (95% CI: 358.3–1714) and 1346 (95% CI: 732.6–1958) at months four and seven, respectively. The concentrations of specific antibodies tended to be higher in patients who reported SARS-CoV-2 infection after vaccination (Fig. 4). However, these differences were not statistically significant. Moreover, the specific responses may be confounded by passively transmitted virus-specific antibodies. Anti-RBD SARS-CoV-2-specific antibodies were detected in all IRT solutions (10 batches). The mean concentration of detected antibodies was 1875 U/mL (min: 102, max: 3062, 95% CI: 1109–2550).

Clinical outcomes

AEs were reported in 61.1% of the enrolled patients (n = 11/18). The most common AEs were local reactions (61.1%, n = 11/18) with exanthema (55.6%, n = 10/18) and local pain (61.1%, n = 11/18). Systemic AEs were present in 38.9% (n = 7/18) of patients and consisted of headaches (27.8%, n = 5/18), fever (16.7%, n = 3/18), myalgia (11.1%, n = 2/18), and fatigue (11.1%, n = 2/18) (Fig. 5). No AE was assessed as SAE. The mean AE duration was 4.5 d (min: 1 d, max: 8 d, 95% CI: 3.0–6.1). The mean visual analog scale pain intensity was 3.46 points (min 1, max 6, 95% CI: 2.32–4.59), and the mean overall AE severity assessment was 29.6 points (min 10, max 80, 95% CI: 16.24–42.85). Emergency medication (paracetamol) for AE treatment was needed in only one patient.

SARS-CoV-2 infection was confirmed by RT-PCR in 50% of the vaccinated patients (n = 9/18). They were five females and four males with a mean age of 49.2 y (min: 40, max 59, 95% CI: 44.1–54.3). Five responded to vaccination, and four belonged to the non-response group. All infections occurred within four months after vaccination, and no cases of a severe or critical form of COVID-19 were reported. One patient (11.1%) was asymptomatic. The other six patients (66.6%) showed mild symptoms. In three patients, antiviral therapy with molnupiravir was administered. Two patients (22.2%) were classified as having moderate disease owing to pneumonia or high fever. No patients required hospitalization or non-invasive ventilation.

In the present study, we present the findings from a prospective observational study focused on the immunogenicity, safety, and clinical outcomes of the booster (third) dose of the mRNA vaccine, Comirnaty. The booster vaccine was administered six months after the completion of the primary vaccination schedule. At the time of booster vaccination, the humoral response persisted in 16.7% of the vaccinated patients with CVID only. This contrasts with the general population in which a humoral response is present in most vaccinated individuals [29, 30].

After one month following booster vaccination, the response rate increased to 72.2%, and the mean serum concentration of anti-RBD SARS-CoV-2 antibodies increased from 13.95 to 302.6 U/mL. However, humoral responses were significantly lower than those of the HDs. The levels of virus-specific antibodies further increased to 1346 U/mL at seven months of the follow-up period. These findings are in striking contrast with our previous results on antibody response dynamics after primary vaccination, which was characterized by a continuous decline [31]. Because of the high infection rate (50%) after the third dose, we investigated whether infection further boosts the humoral response. Higher levels of specific antibodies were observed in patients with hybrid immunity who experienced SARS-CoV-2 infection after vaccination. However, these differences were not statistically significant. This observation is consistent with those of previously published studies. Hybrid immunity is more effective than SARS-CoV-2 infection alone and is associated with a lower hospital admission rate, lower disease severity, and higher magnitude and durability of protection [32, 33].

A high humoral response may also be caused by passively transmitted anti-SARS-CoV-2 antibodies detected in all immunoglobulin solutions used for IRT. The presence of specific antibodies in commercially available immunoglobulin products has been previously described[34, 35]. Thus, IRT may provide better protection. However, this may lead to false-positive serological test results.

The role of humoral immunity and the positive effects of passively transmitted antibodies have been demonstrated in several trials using convalescent plasma [36, 37] and anti-SARS-CoV-2 specific monoclonal antibodies, such as bamlanivimab, etesevimab, casirivimab, and imdevimab [38, 39]. Nevertheless, both therapeutic approaches have limited efficacy against different viral strains, such as the Omicron variant[35, 40]. In addition, the Omicron variant demonstrated enhanced transmissibility and escape from post-vaccination immunity after the administration of first-generation vaccines, although they remained efficacious against severe disease and death [19, 41]. Similarly, we observed significantly lower titers of virus-neutralizing antibodies against Omicron compared to the Delta variant, despite the third (booster) dose of the monovalent BNT162b2 vaccine and regular IRT in HDs; the titers of VNT against both variants were substantially lower in patients with CVID. Moreover, SARS-CoV-2 infection was confirmed by RT-PCR in nine (50%) vaccinated patients. Five patients developed infections despite a detectable humoral response. However, no patients required hospitalization or ventilation. These findings are consistent with those of previous studies. The monovalent BNT162b2 vaccine is less effective against the transmission of the Omicron variant [42, 43] but still prevents severe disease and poor outcomes[19, 44, 45]. Regarding the safety of booster vaccination, AEs were reported by 61.1% of the patients. The most common AEs were local reactions. No AE was assessed as SAE. This corresponds to the observations in the general population [46]

Despite the limitations of this study, including the small number of patients with rare diseases and missing specific T-cell response assessments, it provides crucial evidence of the role of vaccination and IRT in the prevention of severe COVID-19. Booster vaccination and regular IRT may provide long-term high serum levels of anti-RBD SARS-CoV-2 specific antibodies in patients with primary antibody deficiencies. However, humoral responses are restricted to different viral strains. Despite limited protection against infection, booster vaccinations with first-generation and appropriate IRT may reduce the risk of severe outcomes. However, booster vaccinations using adapted vaccines should be considered when available. Due to the passive transmission of specific antibodies, serological tests may provide false-positive results and complicate the diagnosis of infection and post-vaccination response assessment. No new safety concerns were raised after the administration of the third dose. Local reactions were the most frequent Aes, and no SAE occurred.

ACKNOWLEDGMENTS

We would like to recognize laboratory technicians from the Department of Immunology for their contribution to routine laboratory work and physicians from the Vaccination Center Motol University Hospital who administered the vaccines.

FUNDING

This study was supported by the Czech Health Research Council [AZV Project No. NU22-05-00402; Dr. Tomas Kalina]. The funding agencies had no role in the study design; collection, analysis, and interpretation of data; writing of the report; or decision to submit the article for publication.

CONFLICTS OF INTERESTS

Tomas Milota, Jitka Smetanova, Aneta Skotnicova, Hana Zelena, Michal Rataj, Jan Lastovicka, Jirina Bartunkova, and Tomas Kalina declare no conflict of interest relevant to this study.

DATA AVAILABILITY

The datasets generated and analyzed during the study are available from the corresponding author on reasonable request.

DECLARATION OF GENERATIVE AI AND AI-ASSISTED TECHNOLOGIES IN THE WRITTING PROCESS

Neither AI nor AI-assisted technologies were used in the writing process.

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Immunogenicity and clinical outcomes of booster mRNA vaccine BNT162b2 in primary antibody deficiencies

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INTRODUCTION

METHODS

Ethics statement

Study design

Study population

Humoral response assessment

Clinical outcomes

Statistical analysis

RESULTS

Baseline characteristics of the cohort

Humoral response

Clinical outcomes

DISCUSSION

Declarations

References

Supplementary Files

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