An immunologist's perspective on anti-COVID-19 vaccines.

PURPOSE OF REVIEW: Antisevere acute respiratory syndrome-corona virus 2 (SARS-CoV-2) vaccines may provide prompt, effective, and safe solution for the COVID-19 pandemic. Several vaccine candidates have been evaluated in randomized clinical trials (RCTs). Furthermore, data from observational studies mimicking real-life practice and studies on specific groups, such as pregnant women or immunocompromised patients who were excluded from RCTs, are currently available. The main aim of the review is to summarize and provide an immunologist's view on mechanism of action, efficacy and safety, and future challenges in vaccination against SARS-CoV-2. RECENT FINDINGS: mRNA and recombinant viral vector-based vaccines have been approved for conditional use in Europe and the USA. They show robust humoral and cellular responses, high with efficacy in prevention of COVID-19 infection (66.9 95%) and favorable safety profile in RCTs. High efficacy of 80-92% was observed in real-life practice. A pilot study also confirmed good safety profile of the mRNA vaccines in pregnant women. Unlike in those with secondary immunodeficiencies where postvaccination responses did not occur, encouraging results were obtained in patients with inborn errors of immunity. SUMMARY: Although both RCTs and observational studies suggest good efficacy and safety profiles of the vaccines, their long-term efficacy and safety are still being discussed. Despite the promising results, clinical evidence for specific groups such as children, pregnant and breastfeeding women, and immunocompromised patients, and for novel virus variants are lacking. VIDEO ABSTRACT: http://links.lww.com/COAI/A21.

SARS-CoV-2 mRNA vaccines decouple anti-viral immunity from humoral autoimmunity.

mRNA-based vaccines dramatically reduce the occurrence and severity of COVID-19, but are associated with rare vaccine-related adverse effects. These toxicities, coupled with observations that SARS-CoV-2 infection is associated with autoantibody development, raise questions whether COVID-19 vaccines may also promote the development of autoantibodies, particularly in autoimmune patients. Here we used Rapid Extracellular Antigen Profiling to characterize self- and viral-directed humoral responses after SARS-CoV-2 mRNA vaccination in 145 healthy individuals, 38 patients with autoimmune diseases, and 8 patients with mRNA vaccine-associated myocarditis. We confirm that most individuals generated robust virus-specific antibody responses post vaccination, but that the quality of this response is impaired in autoimmune patients on certain modes of immunosuppression. Autoantibody dynamics are remarkably stable in all vaccinated patients compared to COVID-19 patients that exhibit an increased prevalence of new autoantibody reactivities. Patients with vaccine-associated myocarditis do not have increased autoantibody reactivities relative to controls. In summary, our findings indicate that mRNA vaccines decouple SARS-CoV-2 immunity from autoantibody responses observed during acute COVID-19.

Safety and immunogenicity of heterologous recombinant protein subunit vaccine (ZF2001) booster against COVID-19 at 3-9-month intervals following two-dose inactivated vaccine (CoronaVac).

Background: In response to SARS-CoV-2 mutations and waning antibody levels after two-dose inactivated vaccines, we assessed whether a third dose of recombinant protein subunit vaccine (ZF2001) boosts immune responses. Methods: An open-label single-center non-random trial was conducted on people aged 18 years and above at five sites in China. All participants received a two-dose inactivated vaccine (CoronaVac) as their prime doses within 3-9 months of the trial. Primary outcomes were safety and immunogenicity, primarily the geometric mean titers (GMTs) of neutralizing antibodies to live wildtype SARS-CoV-2. Results: A total of 480 participants (median age, 51; range 21-84 years) previously vaccinated with two-dose CoronaVac received a third booster dose of ZF2001 3-4, 5-6, or 7-9-months later. The overall incidence of adverse reactions within 30 days after vaccination was 5.83% (28/480). No serious adverse reactions were reported after the third dose of ZF2001. GMTs in the 3-4-, 5-6-, and 7-9-month groups before vaccination were 3.96, 4.60, and 3.78, respectively. On Day 14, GMTs increased to 33.06, 47.51, and 44.12, respectively. After the booster, GMTs showed no significant difference among the three prime-boost interval groups (all P>0.05). Additionally, GMTs in older adults were lower than those in younger adults on Day 14 for the three groups (P=0.0005, P<0.0001, and P<0.0001). Conclusion: Heterologous boosting with ZF2001 was safe and immunogenic, and prime-boost intervals did not affect the immune response. The immune response was weaker in older than younger adults.

Safety Monitoring of Bivalent COVID-19 mRNA Vaccine Booster Doses Among Persons Aged ≥12 Years - United States, August 31-October 23, 2022.

On August 31, 2022, the Food and Drug Administration (FDA) authorized bivalent formulations of BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccines; these vaccines include mRNA encoding the spike protein from the original (ancestral) strain of SARS-CoV-2 (the virus that causes COVID-19) and from the B.1.1.529 (Omicron) variants BA.4 and BA.5 (BA.4/BA.5). These bivalent mRNA vaccines were authorized for use as a single booster dose ≥2 months after completion of primary series or monovalent booster vaccination; Pfizer-BioNTech bivalent booster was authorized for persons aged ≥12 years and Moderna for adults aged ≥18 years.*,† On September 1, 2022, the Advisory Committee on Immunization Practices (ACIP) recommended that all persons aged ≥12 years receive an age-appropriate bivalent mRNA booster dose.§ To characterize the safety of bivalent mRNA booster doses, CDC reviewed adverse events and health impacts reported after receipt of bivalent Pfizer-BioNTech and Moderna booster doses during August 31-October 23, 2022, to v-safe,¶ a voluntary smartphone-based U.S. safety surveillance system established by CDC to monitor adverse events after COVID-19 vaccination, and the Vaccine Adverse Event Reporting System (VAERS),** a U.S. passive vaccine safety surveillance system managed by CDC and FDA (1). During August 31-October 23, 2022, approximately 14.4 million persons aged ≥12 years received a bivalent Pfizer-BioNTech booster dose, and 8.2 million adults aged ≥18 years received a bivalent Moderna booster dose.†† Among the 211,959 registrants aged ≥12 years who reported receiving a bivalent booster dose to v-safe, injection site and systemic reactions were frequently reported in the week after vaccination (60.8% and 54.8%, respectively); fewer than 1% of v-safe registrants reported receiving medical care. VAERS received 5,542 reports of adverse events after bivalent booster vaccination among persons aged ≥12 years; 95.5% of reports were nonserious and 4.5% were serious events. Health care providers and patients can be reassured that adverse events reported after a bivalent booster dose are consistent with those reported after monovalent doses. Health impacts after COVID-19 vaccination are less frequent and less severe than those associated with COVID-19 illness (2).

Two Cases of Acute Myocarditis in Young Male Adults After mRNA Vaccines Against COVID-19: Similarities and Differences.

Background: The advent of the new coronavirus SARS-CoV-2 has created unprecedented situations, both in terms of health and socio-economic level, worldwide. The emergence of vaccines against this highly contagious virus has raised hopes for its effective inhibition. The efficacy of vaccines, in more than a year of their application in clinical practice, is indisputable, both in terms of reducing serious hospitalizations and deaths, especially in high-risk populations. As with any new medication, the quest and investigation for side effects are reasonable. Myocarditis is one of the extremely rare side effects reported in mRNA vaccines, especially in young males. Case presentation: We present two cases of myocarditis that occurred in our hospital in a short time between them and compare them point by point to identify similarities and differences in order to draw conclusions about the severity of this side effect and its outcome. Conclusion: The benefits of vaccination against Covid-19 outweigh possible untoward effects and especially myocarditis. Health workers must close monitor the vaccinated patients for possible future cardiovascular complications.

Reporting adverse events of COVID-19 vaccines: The case of Bulgaria.

As a member state of the European Union, where vaccines against COVID-19 are available and affordable, Bulgaria reports the lowest immunization coverage and the most pronounced vaccine distrust. The present study aimed to assess the self-reported adverse reactions following COVID-19 vaccination as a possible tool to increase the trust in vaccines. A cross-sectional survey-based study, covering 761 vaccinated respondents, was conducted in Plovdiv (469 with an mRNA vaccine and 292 with an adenoviral vector vaccine). Descriptive statistics parametric and non-parametric methods were applied. Statistical significance was set at p<0.05. The median age of the respondents was 42 years, females (72.5%). At least one adverse reaction was reported in 89.9% of those immunized with mRNA vaccine and 93.8% in the adenoviral vector vaccine group (p>0.05). They were mild to moderate and resolved within several days. The levels of local reactions were comparable: 91.7% in those who received mRNA and 89.7% in those who received an adenoviral vector vaccine (p = 0.366). The most common types of systemic reactions were fatigue, headache, and muscle pains. An association was found between the systemic reactions and the type of vaccine administered: 59.7% in mRNA recipients and 89.4% in adenoviral vector vaccinees (p<0.001). None of the registered systemic reactions required medical attention. There were 3 reports of generalized urticaria after an mRNA and 2 after an adenoviral vector vaccine. The reported reactions are relatively high but expected and no adverse events have been reported that are not listed in the official Summary of Product Characteristics.

Adverse effects following COVID-19 vaccination in Iran.

BACKGROUND: Vaccination is a key intervention to prevent COVID-19. Many vaccines are administered globally, yet there is not much evidence regarding their safety and adverse effects. Iran also faces this challenge, especially as data regarding the Sputnik V vaccine is sparse. Therefore, the aim of this study is to determine the adverse effects of the most commonly used vaccines in Iran. METHODS: Using a retrospective cohort study design, 6600 subjects aged 18 years or older who had received two doses of any of the three COVID-19 vaccines (Sinopharm, AstraZeneca, and Sputnik V) were selected using a random sampling method between March and August 2021. Subjects were asked about any adverse effects of the vaccines by trained interviewers via telephone interview. Vaccine-related adverse effects in individuals during the first 72 h and subsequently following both doses of the vaccines were determined. The demographic variables, type of administered vaccine, adverse effects, and history of the previous infection with COVID-19 were collected. Descriptive statistics (mean, standard deviation) and analytical statistics (Chi-squared and Wilcoxon tests) were performed at a 95% significance level using STATA software version 15 (STATA Corp, College Station, TX, USA). RESULTS: From 6600 participants, 4775 responded (response rate = 72.3%). Of the participants, 1460 (30.6%) received the AstraZeneca vaccine, 1564 (32.8%) received the Sinopharm vaccine and 1751 (36.7%) received the Sputnik V vaccine. 2653 participants (55.56%) reported adverse effects after the first dose and 1704 (35.7%) after the second dose. Sputnik V caused the most adverse effects with 1449 (82.7%) vaccine recipients reporting symptoms after the first or second dose, compared with 1030 (70.5%) for AstraZeneca and only 585 (37.4%) for the Sinopharm vaccine. The most common adverse effects after the first dose were fatigue (28.37%), chill/fever (26.86%), and skeletal pain (22.38%). These three adverse effects were the same for the second dose, although their prevalence was lower. CONCLUSIONS: In this study, we demonstrate that the Sputnik V vaccine has the highest rate of adverse effects, followed by the AstraZeneca and Sinopharm vaccines. COVID-19 vaccines used in Iran are safe and there were no reports of serious adverse effects.

Immunogenicity and safety of SpikoGen®, an adjuvanted recombinant SARS-CoV-2 spike protein vaccine as a homologous and heterologous booster vaccination: A randomized placebo-controlled trial.

SpikoGen® is a subunit recombinant spike protein vaccine combined with Advax-CpG55.2™ adjuvant. This COVID-19 vaccine was shown to be safe, immunogenic and efficacious in previous clinical trials. This study aimed to assess the safety and immunogenicity of SpikoGen® vaccine as a homologous and heterologous booster vaccination. This double-blind and randomized placebo-controlled (5:1) trial was performed on 300 already vaccinated participants. SpikoGen® or saline placebo was administered as a booster dose to participants who had received a full two-dose COVID-19 vaccination course. Immunogenicity assessments were done 14 days after the booster dose with the primary immunogenicity outcome seroconversion rate of neutralizing antibodies. Safety outcomes included the incidence of solicited adverse events up to 7 days after the booster dose. SpikoGen® vaccine induced a robust humoral response both as a homologous and heterologous booster, when compared to the placebo. At Day 14, seroconversion of neutralizing antibodies was 76% (95% confidence interval [CI]: 69%-82%) in the SpikoGen® group versus 3% (95% CI: 0%-13%) in the placebo group. The most common local and systemic reported adverse events were injection site pain and fatigue. No serious adverse events were reported. The SpikoGen®-booster induced cross-neutralization of other SARS-CoV-2 variants. Irrespective of the primary vaccine course received, SpikoGen® vaccine showed promising effects as both a homologous and heterologous booster dose. This vaccine also had a good safety profile with no vaccine-associated serious adverse events. On the basis of these results, SpikoGen® vaccine has been approved as a booster dose.

Acute cardiac side effects after COVID-19 mRNA vaccination: a case series.

BACKGROUND: Vaccination against SARS-CoV-2 has been the main tool to contain the pandemic. The rush development of the 3 vaccines and their expedited approval have led to inoculation of millions of patients around the world, leading to a containment of the disease. Despite continuous viral mutations and the identification of weaker variants, the severity of the infections has been mild, with many patients being either asymptomatic or recovering at home. Currently the focus has shifted from the host of organ damage related to the infection to potential side effects of the vaccine. Myocarditis has been reported as one of the potential side effects from the mRNA vaccine, affecting young healthy individuals. Up to September 30, 2021, 1.243 cases of myocarditis after vaccination with BNT162b2 Comirnaty© were registered in young adults by the Paul-Ehrlich-Institute in Germany alone. The exact pathophysiology and the risk factors for myocarditis following vaccination remain unclear. We present a case series of eight patients with cardiac symptom shortly after SARS-CoV-2 mRNA vaccination (BNT162b6, Biontech, Comirnaty© or mRNA-1237 Moderna, Spikevax©). PATIENTS AND METHODS: Eight patients between 13 and 56 years of age, vaccinated with either BNT162b2 or mRNA-1273 mRNA vaccine between January and August 2021 developed cardiac side effects shortly after either their first or second dose of the vaccine. Clinical data were retrieved from the clinical information system and analyzed. To support diagnosis of myocarditis or pericarditis, cardiac magnetic resonance imaging (MRI) was performed shortly after the onset of symptoms, with further investigations in severe cases. Symptoms were defined as dyspnea, chest pain and cardiac arrhythmia as determined by electrocardiography. RESULTS: Eight patients (5 males and 3 females) developed cardiac symptoms compatible with myocarditis, according to the CDC criteria, shortly after SARS-CoV-2 mRNA vaccination. Three patients (2 males, 1 female) required hospitalization due to severe chest pain and elevated troponin levels. All patients recovered fully within 7 days from the symptom onset. CONCLUSIONS: Our data suggest that cardiac adverse events such as myocarditis or pericarditis shortly after SARS-CoV-2 mRNA vaccination are rare but possible and occur particularly in male patients.

Safety and immunogenicity of heterologous boost immunization with an adenovirus type-5-vectored and protein-subunit-based COVID-19 vaccine (Convidecia/ZF2001): A randomized, observer-blinded, placebo-controlled trial.

BACKGROUND: Heterologous boost vaccination has been proposed as an option to elicit stronger and broader, or longer-lasting immunity. We assessed the safety and immunogenicity of heterologous immunization with a recombinant adenovirus type-5-vectored Coronavirus Disease 2019 (COVID-19) vaccine (Convidecia, hereafter referred to as CV) and a protein-subunit-based COVID-19 vaccine (ZF2001, hereafter referred to as ZF). METHODS AND FINDINGS: We conducted a randomized, observer-blinded, placebo-controlled trial, in which healthy adults aged 18 years or older, who have received 1 dose of Convidecia, with no history of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, were recruited in Jiangsu, China. Sixty participants were randomly assigned (2:1) to receive either 1 dose of ZF2001 or placebo control (trivalent inactivated influenza vaccine (TIV)) administered at 28 days after priming, and received the third injection with ZF2001 at 5 months, referred to as CV/ZF/ZF (D0-D28-M5) and CV/ZF (D0-M5) regimen, respectively. Sixty participants were randomly assigned (2:1) to receive either 1 dose of ZF2001 or TIV administered at 56 days after priming, and received the third injection with ZF2001 at 6 months, referred to as CV/ZF/ZF (D0-D56-M6) and CV/ZF (D0-M6) regimen, respectively. Participants and investigators were masked to the vaccine received but not to the boosting interval. Primary endpoints were the geometric mean titer (GMT) of neutralizing antibodies against wild-type SARS-CoV-2 and 7-day solicited adverse reactions. The primary analysis was done in the intention-to-treat population. Between April 7, 2021 and May 6, 2021, 120 eligible participants were randomly assigned to receive ZF2001/ZF2001 (n = 40) or TIV/ZF2001 (n = 20) 28 days and 5 months post priming, and receive ZF2001/ZF2001 (n = 40) or TIV/ZF2001 (n = 20) 56 days and 6 months post priming. Of them, 7 participants did not receive the third injection with ZF2001. A total of 26 participants (21.7%) reported solicited adverse reactions within 7 days post boost vaccinations, and all the reported adverse reactions were mild, with 13 (32.5%) in CV/ZF/ZF (D0-D28-M5) regimen, 7 (35.0%) in CV/ZF (D0- M5) regimen, 4 (10.0%) in CV/ZF/ZF (D0-D56-M6) regimen, and 2 (10.0%) in CV/ZF (D0-M6) regimen, respectively. At 14 days post first boost, GMTs of neutralizing antibodies in recipients receiving ZF2001 at 28 days and 56 days post priming were 18.7 (95% CI 13.7 to 25.5) and 25.9 (17.0 to 39.3), respectively, with geometric mean ratios of 2.0 (1.2 to 3.5) and 3.4 (1.8 to 6.4) compared to TIV. GMTs at 14 days after second boost of neutralizing antibodies increased to 107.2 (73.7 to 155.8) in CV/ZF/ZF (D0-D28-M5) regimen and 141.2 (83.4 to 238.8) in CV/ZF/ZF (D0-D56-M6) regimen. Two-dose schedules of CV/ZF (D0-M5) and CV/ZF (D0-M6) induced antibody levels comparable with that elicited by 3-dose schedules, with GMTs of 90.5 (45.6, 179.8) and 94.1 (44.0, 200.9), respectively. Study limitations include the absence of vaccine effectiveness in a real-world setting and current lack of immune persistence data. CONCLUSIONS: Heterologous boosting with ZF2001 following primary vaccination with Convidecia is more immunogenic than a single dose of Convidecia and is not associated with safety concerns. These results support flexibility in cooperating viral vectored and recombinant protein vaccines. TRIAL REGISTRATION: Study on Heterologous Prime-boost of Recombinant COVID-19 Vaccine (Ad5 Vector) and RBD-based Protein Subunit Vaccine; ClinicalTrial.gov NCT04833101.

A Case Report of Herpes Zoster Ophthalmicus and Meningitis After COVID-19 Vaccination.

There are several reports that herpes zoster characterized by reactivation of varicella zoster virus (VZV) following coronavirus disease 2019 (COVID-19) vaccines can occur. Herein, we report VZV meningitis, herpes zoster ophthalmicus (HZO), and late neurotrophic keratitis after receiving a second dose of messenger RNA (mRNA) COVID-19 vaccine. A 74-year-old man developed a vesicular skin rash on the forehead, scalp, nose, and left upper eyelid with a severe headache. Five days earlier, he received a second dose of the BNT162b2 mRNA vaccine on his left arm. Ocular examination revealed conjunctival hyperemia and pseudodendrite in the peripheral cornea. VZV was detected in the cerebrospinal fluid using polymerase chain reaction. The patient was diagnosed with HZO and meningitis. The patient was treated with intravenous acyclovir and topical acyclovir ointment and levofloxacin 1.5% eye drops. One month later, he developed a central epithelial defect with a rolled margin, typical of a neurotrophic ulcer. Treatment with a therapeutic contact lens and a combination of topical recombinant human epithelial growth factor and ofloxacin ointment was initiated. At six months after vaccination, the slit-lamp examination findings were stable with a mild corneal superficial stromal haze.

Safety of Inactivated and mRNA COVID-19 Vaccination Among Patients Treated for Hypothyroidism: A Population-Based Cohort Study.

Background: Thyroiditis and Graves' disease have been reported after coronavirus disease 2019 (COVID-19) vaccination. We evaluated the risks of adverse events after COVID-19 vaccination among patients treated for hypothyroidism. Methods: In this retrospective population-based cohort study of Hong Kong Hospital Authority electronic health records with the Department of Health vaccination records linkage, levothyroxine (LT4) users were categorized into unvaccinated, vaccinated with BNT162b2 (mRNA vaccine), or CoronaVac (inactivated vaccine) between February 23, 2021, and September 9, 2021. Study outcomes were dosage reduction or escalation in LT4, emergency department (ED) visit, unscheduled hospitalization, adverse events of special interest (AESI) according to the World Health Organization's Global Advisory Committee on Vaccine Safety, and all-cause mortality. Inverse probability of treatment weighting for propensity score was applied to balance baseline patient characteristics among the three groups. Hazard ratios (HR) were estimated using Cox regression models. Patients were observed from the index date until the occurrence of study outcome, death, or censored on September 30, 2021, whichever came first. Results: In total, 47,086 LT4 users were identified (BNT162b2: n = 12,310; CoronaVac: n = 11,353; and unvaccinated: n = 23,423). COVID-19 vaccination was not associated with increased risks of LT4 dosage reduction (BNT162b2: HR = 0.971 [confidence interval; CI 0.892-1.058]; CoronaVac: HR = 0.968 [CI 0.904-1.037]) or escalation (BNT162b2: HR = 0.779 [CI 0.519-1.169]; CoronaVac: HR = 0.715 [CI 0.481-1.062]). Besides, COVID-19 vaccination was not associated with a higher risk of ED visits (BNT162b2: HR = 0.944 [CI 0.700-1.273]; CoronaVac: HR = 0.851 [CI 0.647-1.120]) or unscheduled hospitalization (BNT162b2: HR = 0.905 [CI 0.539-1.520]; CoronaVac: HR = 0.735 [CI 0.448-1.207]). There were two (0.016%) deaths and six (0.062%) AESI recorded for BNT162b2 recipients, and one (0.009%) and three (0.035%) for CoronaVac recipients, respectively. Conclusions: BNT162b2 or CoronaVac vaccination is not associated with unstable thyroid status or an increased risk of adverse outcomes among patients treated for hypothyroidism in general. These reassuring data should encourage them to get vaccinated against COVID-19 for protection from potentially worse COVID-19-related outcomes.