Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination.

During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including third-dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination.

ChAdOx1-S adenoviral vector vaccine applied intranasally elicits superior mucosal immunity compared to the intramuscular route of vaccination.

COVID-19 vaccines prevent severe forms of the disease, but do not warrant complete protection against breakthrough infections. This could be due to suboptimal mucosal immunity at the site of virus entry, given that all currently approved vaccines are administered via the intramuscular route. In this study, we assessed humoral and cellular immune responses in BALB/c mice after intranasal and intramuscular immunization with adenoviral vector ChAdOx1-S expressing full-length Spike protein of SARS-CoV-2. We showed that both routes of vaccination induced a potent IgG antibody response, as well as robust neutralizing capacity, but intranasal vaccination elicited a superior IgA antibody titer in the sera and in the respiratory mucosa. Bronchoalveolar lavage from intranasally immunized mice efficiently neutralized SARS-CoV-2, which has not been the case in intramuscularly immunized group. Moreover, substantially higher percentages of epitope-specific CD8 T cells exhibiting a tissue resident phenotype were found in the lungs of intranasally immunized animals. Finally, both intranasal and intramuscular vaccination with ChAdOx1-S efficiently protected the mice after the challenge with recombinant herpesvirus expressing the Spike protein. Our results demonstrate that intranasal application of adenoviral vector ChAdOx1-S induces superior mucosal immunity and therefore could be a promising strategy for putting the COVID-19 pandemic under control.

Premarket Development Times for Innovative Vaccines--To What Extent Are the Coronavirus Disease 2019 (COVID-19) Vaccines Outliers?

One reason expressed in surveys of people reporting coronavirus disease 2019 (COVID-19) vaccine hesitancy is how rapidly these vaccines have reached the market. To estimate the length of time the COVID-19 vaccine spent in research and development as compared to other novel vaccines, we apply previously established methods for estimating medical product development times, using the key associated patent filings cited by the manufacturer as the marker of when commercial development activity began. Applying these methods to a cohort of recently approved innovative vaccines and comparing them to the first-approved COVID-19 vaccine (BioNTech/Pfizer), we found key patent filings for the technology in this COVID-19 vaccine occurred 10.0 years prior to regulatory authorization. By this metric, the development timelines for innovative vaccines have been shortening since the 1980s, and the COVID-19 vaccine comfortably fits within this pattern. Vaccine development timelines have now even drawn to parity with many of the most commonly used drugs.

Effectiveness of AstraZeneca vaccine against SARS-CoV-2 (ChAdox1-S) in reducing in-hospital mortality in individuals with COVID-19 and schizophrenia: A retrospective cohort study.

ChAdOx1-S is a viral vector vaccine developed by AstraZeneca. We aimed to assess the effectiveness of 1 and 2 doses of the ChAdOx1-S vaccine in reducing COVID-19-related in-hospital mortality in individuals with schizophrenia. This is a retrospective cohort study using a nationwide hospital database in Brazil. Individuals diagnosed with COVID-19 and schizophrenia were included in the study. The exposures were 0, 1, and 2 doses of ChAdOx1-S. The outcome of mortality was measured in hazard ratios (HR), calculated using multivariable Cox regression models. The study included 1,929 positive cases of COVID-19 in schizophrenia patients. After adjusting for age, socioeconomic factors, and comorbidities, we observed a significant 55% decrease in the hazard of mortality in the 2-dose vaccination group (HR 0.45, 95% CI: 0.310-0.652) compared to the unvaccinated. Surprisingly, our results did not show any significant reduction in the hazard of mortality in the 1 dose vaccination group (HR 1.278, 95% CI: 0.910-1.795). The effectiveness of two doses of ChAdOx1-S in individuals with schizophrenia aligns with findings from studies on the general population. That one dose was insignificant. Overall, these findings are important for informing public health decisions - prioritizing individuals with schizophrenia for vaccinations and managing acceptance of vaccines.

ABO blood group associated with cerebral venous thrombosis after Oxford-AstraZeneca COVID-19 vaccination: a case-control study.

OBJECTIVES: To determine whether blood group influences development of cerebral venous thrombosis (CVT) after administration of the coronavirus disease 2019 (COVID-19) AstraZeneca ChAdOx1-S vaccine. DESIGN: A case-control study. Univariate and multivariate logistic regression was used to determine the association between blood type and COVID-19 vaccination status. SETTING: Vaccinated and unvaccinated patients recruited from the international Bio-Repository to Establish the Aetiology of Sinovenous Thrombosis study and the Cerebral Venous Sinus Thrombosis With Thrombocytopenia Syndrome Study Group. PARTICIPANTS: All patients were of European descent and age and sex matched. Cases (n = 82) were patients ≥18 years old who suffered a CVT within 28 days of a first dose of ChAdOx1-S vaccine. Controls (n = 441) were unvaccinated CVT patients ≥18 years old. All patients were of European descent. MAIN OUTCOME MEASURES: Frequency of blood type and ABO allele distribution by vaccination status. RESULTS: Blood group O was found to be more prevalent among CVT patients with vaccine-induced thrombotic thrombocytopenia (VITT-CVT) after ChAdOx1-S vaccination compared with unvaccinated CVT cases (43% vs. 17%, respectively, p < 0.001). Blood group A was less prevalent, though still high, in the vaccinated group compared with the unvaccinated group (47% vs. 71%, respectively, p < 0.001). No significant differences were observed in the VITT-CVT non-ChAdOx1-S vaccine group and unvaccinated pre-COVID-19 CVT group for blood group. CONCLUSIONS: Blood group O is more prevalent among patients with VITT-CVT after ChAdOx1-S vaccination compared with unvaccinated cases, independent of well-established CVT risk factors. A larger dataset may be able to determine whether those of blood groups B and/or AB may be safely vaccinated with the low cost, readily available and easily transported ChAdOx1-S rather than adopting a complete ban.

Association between COVID-19 Vaccination (ChAdOx1-S) and Thromboembolic, Thrombocytopenic, Hemorrhagic Events: A Systematic Review and Meta-analysis of Analytical Epidemiological Studies.

We conducted a systematic review of analytical epidemiological studies to assess the association between ChAdOx1-S vaccination and thromboembolic, thrombocytopenic, and hemorrhagic events. We searched Medline, Embase, Google Scholar, WHO-COVID-19 database, and medRxiv for studies evaluating the association between ChAdOx1-S and vascular events. Primary outcomes of interest were cerebral venous sinus thrombosis, peripheral venous thrombosis (PVT), and thrombocytopenia. Two independent reviewers screened for eligible studies, extracted data, and assessed the risk of bias. The DerSimonian-Laird random effects model was used to pool the incidence rate ratios (IRRs) separately for the first and second doses. Heterogeneity was assessed using I2 statistics. Twenty studies were included, of which 11 were self-controlled case series, and nine were cohort studies (254 million participants). Pooling of 17 studies showed a higher risk of cerebrovascular thrombosis (IRR = 3.5, 95% CI = 2.2-5.4, I2 = 79%), PVT (IRR = 2.0, 95% CI = 1.1-3.5, I2 = 95%) and thrombocytopenia (IRR = 1.6, 95% CI = 1.4-1.9, I2 = 93%) among those who received ChAdOx1-S vaccination as compared to controls. No increased risk was seen after the second dose or for secondary outcomes. There is moderate-to-high certainty of the evidence for the increased risk of cerebral venous sinus thrombosis, PVT, and thrombocytopenia following the first dose of the ChAdOx1-S vaccine. Systematic Review Registration: PROSPERO CRD42022372768.

Association of the Magnitude of Anti-SARS-CoV-2 Vaccine Side Effects with Sex, Allergy History, Chronic Diseases, Medication Intake, and SARS-CoV-2 Infection.

Vaccination provides the best protection against the increasing infections of SARS-CoV-2. The magnitude and type of anti-SARS-CoV-2 vaccine side effects (SEs) depend on parameters that are not fully understood. In this cross-sectional study, the associations between different anti-SARS-CoV-2 vaccine SEs and age, sex, the presence of chronic diseases, medication intake, history of allergies, and infections with SARS-CoV-2 were investigated. Our survey used the Google platform and had 866 participants, contacted through e-mails, social media and chain referral sampling (margin of error ≈ 4.38%, 99% confidence). More than 99% of the participants received the BNT162b2 and ChAdOx1-S vaccines. Being female, having chronic diseases, taking medicines routinely and the presence of a SARS-CoV-2 infection (p < 0.05) were associated with strong SEs after the BNT162b2 vaccine second dose. Having a history of allergies and a female sex (p < 0.01) were associated with strong SEs after the ChAdOx1-S vaccine second dose. Furthermore, the results reveal, for the first time, the associations between having a history of allergies, chronic diseases, medication usage, and SEs of a strong magnitude for the BNT162b2 and ChAdOx1-S vaccines. Additionally, this study supports the association of the female sex and infection with SARS-CoV-2 with an increased potential of developing stronger SEs with certain anti-SARS-CoV-2 vaccines.

Equal Maintenance of Anti-SARS-CoV-2 Antibody Levels Induced by Heterologous and Homologous Regimens of the BNT162b2, ChAdOx1, CoronaVac and Ad26.COV2.S Vaccines: A Longitudinal Study Up to the 4th Dose of Booster.

Several technological approaches have been used to develop vaccines against COVID-19, including those based on inactivated viruses, viral vectors, and mRNA. This study aimed to monitor the maintenance of anti-SARS-CoV-2 antibodies in individuals from Brazil according to the primary vaccination regimen, as follows: BNT162b2 (group 1; 22) and ChAdOx1 (group 2; 18). Everyone received BNT162b2 in the first booster while in the second booster CoronaVac, Ad26.COV2.S, or BNT162b2. Blood samples were collected from 2021 to 2023 to analyze specific RBD (ELISA) and neutralizing antibodies (PRNT50). We observed a progressive increase in anti-RBD and neutralizing antibodies in each subsequent dose, remaining at high titers until the end of follow-up. Group 1 had higher anti-RBD antibody titers than group 2 after beginning the primary regimen, with significant differences after the 2nd and 3rd doses. Group 2 showed a more expressive increase after the first booster with BNT162B2 (heterologous booster). Group 2 also presented high levels of neutralizing antibodies against the Gamma and Delta variants until five months after the second booster. In conclusion, the circulating levels of anti-RBD and neutralizing antibodies against the two variants of SARS-CoV-2 were durable even five months after the 4th dose, suggesting that periodic booster vaccinations (homologous or heterologous) induced long-lasting immunity.

Humoral responses to wild type and ancient BA.1 SARS-CoV-2 variant after heterologous priming vaccination with ChAdOx1 nCoV-19 and BNT162b2 booster dose.

Several countries have recommended a booster dose of Pfizer BNT162b2 vaccine for subjects under the age of 60, who have already received the first dose of ChAdOx1. This is due to several ChAdOx1 vaccine-associated adverse vascular events and thrombocytopenia. Neutralization assay and quantitative IgG anti-SARS-CoV-2 Spike antibody (anti-S-IgG) were conducted to investigate the long-term responses to vaccine treatment in a cohort of Sardinian participants, who have received heterologous Prime-Boost Vaccination via ChAdOx1 vector vaccine and a booster dose via BNT162b2. The obtained results were compared with those of a cohort of healthcare workers (HCW) who received homologous BNT162b2 (BNT/BNT/BNT) vaccination. One month (T2) and five months after the second and before the third dose (T3), anti-spike antibody or neutralizing titers in the subjects vaccinated with ChAdOx1-S/BNT162b2 were significantly higher than those who experienced the ChAdOx1-S/ChAdOx1-S or BNT162b2/BNT162b2 schedule. These results suggest that a ChAdOx1-S/BNT162b2 regimen provides a more robust antibody response than either of the homologous regimens. However, the anti-spike antibodies or neutralizing titers after the third injection (mRNA vaccine) of ChAdOx1-S as a second dose and BNT162b2 were not statistically different. Homologous and heterologous vaccination provided a strong antibody response. Neutralizing activities were also described against the Omicron BA.1 variant in a sub-group (40) representative of the three vaccination regimens among our cohort.

Clinical outcomes and risk factors for SARS-CoV-2 breakthrough cases following vaccination with BNT162b2, CoronaVac, or ChAdOx1-S: A retrospective cohort study in Malaysia.

Background: The SARS-CoV-2 pandemic drove global vaccination. However, breakthrough infections raised concerns about vaccine performance, leading the World Health Organization (WHO) to recommend investigations thereof. This study aimed to evaluate the clinical outcomes (time to breakthrough infection, intensive care unit [ICU] admission, and in-hospital mortality) of hospitalised patients with SARS-CoV-2 breakthrough infection. This was the primary outcome and the risk factors associated with its severity were the secondary outcomes. Methods: This retrospective cohort study at a multispecialty tertiary hospital in Selangor, Malaysia included 200 fully adult vaccinated patients, with confirmed SARS-CoV-2 infection, admitted from September 2021 to February 2022. Participants were selected by simple random sampling. Infection severity was categorised as CAT 2-3 (mild-moderate) and 4-5 (severe-critical). Results: The time to breakthrough infection was significantly longer for BNT162B2 recipients (128.47 ± 46.21 days) compared to CoronaVac (94.09 ± 48.71 days; P = 0.001) and ChAdOx1-S recipients (90.80 ± 37.59 days; P = 0.019). No significant associations were found between SARS-CoV-2-related ICU admission, mortality, and the vaccines. Multivariable analysis identified vaccine type, variant of concern, ethnicity, and hypertension as significant predictors of severity. BNT162b2 and ChAdOx1-S recipients had significantly (81 % and 74 %, respectively) lower odds of CAT 4-5 infection compared to CoronaVac recipients. Indian patients had a significantly (83 %) lower chance of CAT 4-5 infection compared to Malay patients. Patients with breakthrough infections during the Omicron period had a significantly (58 %) lower risk of CAT 4-5 compared to those in the Delta period. The CAT 4-5 risk was significantly (nearly threefold) higher in hypertensive patients. Conclusion: The results support the Malaysian Ministry of Health's recommended booster three months after primary vaccination and the WHO's recommended heterologous booster following CoronaVac. Certain ethnic groups, hypertensive patients, and viral variants may require attention in future pandemics.

Immune Evasion of SARS-CoV-2 Omicron Subvariants XBB.1.5, XBB.1.16 and EG.5.1 in a Cohort of Older Adults after ChAdOx1-S Vaccination and BA.4/5 Bivalent Booster.

The recently emerged SARS-CoV-2 Omicron sublineages, including the BA.2-derived XBB.1.5 (Kraken), XBB.1.16 (Arcturus), and EG.5.1 (Eris), have accumulated several spike mutations that may increase immune escape, affecting vaccine effectiveness. Older adults are an understudied group at significantly increased risk of severe COVID-19. Here we report the neutralizing activities of 177 sera samples from 59 older adults, aged 62-97 years, 1 and 4 months after vaccination with a 4th dose of ChAdOx1-S (Oxford/AstraZeneca) and 3 months after a 5th dose of Comirnaty Bivalent Original/Omicron BA.4/BA.5 vaccine (Pfizer-BioNTech). The ChAdOx1-S vaccination-induced antibodies neutralized efficiently the ancestral D614G and BA.4/5 variants, but to a much lesser extent the XBB.1.5, XBB.1.16, and EG.5.1 variants. The results showed similar neutralization titers between XBB.1.16 and EG.5.1 and were lower compared to XBB.1.5. Sera from the same individuals boosted with the bivalent mRNA vaccine contained higher neutralizing antibody titers, providing a better cross-protection against Omicron XBB.1.5, XBB.1.16 and EG.5.1 variants. Previous history of infection during the epidemiological waves of BA.1/BA.2 and BA.4/BA.5, poorly enhanced neutralization activity of serum samples against XBBs and EG.5.1 variants. Our data highlight the continued immune evasion of recent Omicron subvariants and support the booster administration of BA.4/5 bivalent vaccine, as a continuous strategy of updating future vaccine booster doses to match newly emerged SARS-CoV-2 variants.

Impact of vaccine platform and BCG vaccination on antibody responses to COVID-19 vaccination.

Multiple factors, including vaccine platform and prior vaccinations, influence vaccine responses. We compared antibody responses to CoronaVac (Sinovac) and ChAdOx1-S (AstraZeneca-Oxford) vaccination in 874 healthcare workers in Brazil. As participants were randomised to BCG vaccination or placebo in the preceding 0-6 months as part of the BCG vaccination to reduce the impact of COVID-19 in healthcare workers (BRACE) trial, we also investigated the influence of recent BCG vaccination on antibody responses to these COVID-19 vaccines. Twenty-eight days after the second dose of each vaccine, ChAdOx1-S induced a stronger anti-spike IgG response than CoronaVac vaccination. Recent BCG vaccination did not impact IgG antibody responses to ChAdOx1-S or CoronaVac.

Heterologous prime-boost immunization with ChAdOx1-S and BNT162b2: reactogenicity and immunogenicity in a prospective cohort study.

OBJECTIVES: Regarding reactogenicity and immunogenicity, heterologous COVID-19 vaccination regimens are considered as an alternative to conventional immunization schemes. METHODS: Individuals receiving either heterologous (ChAdOx1-S [AstraZeneca, Cambridge, UK]/BNT162b2 [Pfizer-BioNTech, Mainz, Germany]; n = 306) or homologous (messenger RNA [mRNA]-1273 [Moderna, Cambridge, Massachusetts, USA]; n = 139) vaccination were asked to participate when receiving their second dose. Reactogenicity was assessed after 1 month, immunogenicity after 1, 3, and/or 6 months, including a third dose, through SARS-CoV-2 antispike immunoglobulin G, surrogate virus neutralization test, and a plaque reduction neutralization test against the Delta (B.1.167.2) and Omicron (B.1.1.529; BA.1) variants of concern. RESULTS: The overall reactogenicity was lower after heterologous vaccination. In both cohorts, SARS-CoV-2 antispike immunoglobulin G concentrations waned over time with the heterologous vaccination demonstrating higher neutralizing activity than homologous mRNA vaccination after 3 months to low neutralizing levels in the Delta plaque reduction neutralization test after 6 months. At this point, 3.2% of the heterologous and 11.4% of the homologous cohort yielded low neutralizing activity against Omicron. After a third dose of an mRNA vaccine, ≥99% of vaccinees demonstrated positive neutralizing activity against Delta. Depending on the vaccination scheme and against Omicron, 60% to 87.5% of vaccinees demonstrated positive neutralizing activity. CONCLUSION: ChAdOx1-S/BNT162b2 vaccination demonstrated an acceptable reactogenicity and immunogenicity profile. A third dose of an mRNA vaccine is necessary to maintain neutralizing activity against SARS-CoV-2. However, variants of concern-adapted versions of the vaccines would be desirable.

A rare case of bilateral optic neuritis post-Covishield (ChAdOx1-S [recombinant]) vaccination.

Multiple adverse effects have been reported in people receiving the COVID-19 vaccinations including few reports of optic neuritis. However, there is no report till date, of bilateral optic neuritis post-ChAdOx1-S (recombinant) vaccination. We report here, for the first time, such a case in a previously healthy woman. Although a direct causal relationship cannot be proven, there was a temporal association between the vaccination and the onset of optic neuritis. Some vaccine adjuvants inciting disproportionate systemic inflammation, molecular mimicry, and the hypercoagulable state seen after COVID-19 vaccination could be the possible causes for the development of optic neuritis. Clinicians should be aware of this adverse effect apart from various other adverse effects of COVID-19 vaccination.

Immunogenicity, safety and reactogenicity of heterologous (third dose) booster vaccination with a full or fractional dose of two different COVID-19 vaccines: A phase 4, single-blind, randomized controlled trial in adults.

In this phase 4 study we assessed boosting with fractional doses of heterologous COVID-19 vaccines in Brazilian adults primed with two doses of CoronaVac (Sinovac/Butantan, São Paulo, Brazil) at least 4 months previously. Participants received either full-dose of ChAdOx1-S (Group 1, n = 232), a half dose of ChAdOx1-S (Group 2, n = 236), or a half dose of BNT162b2 (Group 3, n = 234). The primary objective was to show 80% seroresponse rates (SRR) 28 d after vaccination measured as IgG antibodies against a prototype SARS-CoV-2 spike-protein. Safety was assessed as solicited and unsolicited adverse events. At baseline all participants were seropositive, with high IgG titers overall. SRR at Day 28 were 34.3%, 27.1% and 71.2%, respectively, not meeting the primary objective of 80%, despite robust immune responses in all three groups with geometric mean-fold rise (GMFR) in IgG titers of 3.39, 2.99 and 7.42, respectively. IgG immune responses with similar GMFR were also observed against SARS-CoV-2 variants, Alpha, Beta, Delta, Gamma and D614G. In subsets (n = 35) of participants GMFR of neutralizing immune responses against live prototype SARS-CoV-2 virus and Omicron BA.2 were similar to the IgG responses as were pseudo-neutralizing responses against SARS-CoV-2 prototype and Omicron BA.4/5 variants. All vaccinations were well tolerated with no vaccine-related serious adverse events and mainly transient mild-to-moderate local and systemic reactogenicity. Heterologous boosting with full or half doses of ChAdOx1-S or a half dose of BNT162b2 was safe and immunogenic in CoronaVac-primed adults, but seroresponse rates were limited by high baseline immunity.

Humoral and T Cell Immune Responses against SARS-CoV-2 after Primary and Homologous or Heterologous Booster Vaccinations and Breakthrough Infection: A Longitudinal Cohort Study in Malaysia.

Vaccine efficacy against SARS-CoV-2 could be compromised by the emergence of SARS-CoV-2 variants and it is important to study how it impacts the booster vaccination regime. We investigated the humoral and T cell responses longitudinally in vaccinated uninfected (n = 25) and post-COVID-19 individuals (n = 8), and those who had received a BNT162b2 booster following complete two-doses regimes of either BNT162b2 (homologous) (n = 14) or ChAdOx1-S (heterologous) (n = 15) vaccines, by means of a SARS-CoV-2 pseudovirus neutralization test and QuantiFERON SARS-CoV-2 assay. Vaccinated post-COVID-19 individuals showed higher neutralizing antibodies with longer durability against SARS-CoV-2 wild type (WT) and Omicron spikes, but demonstrated similar declining T cell responses compared to the uninfected vaccinated. Two doses of BNT162b2 induced higher neutralizing antibodies against WT and T cell responses than ChAdOx1-S for six months. The BNT162b2 booster confers a greater humoral response against WT, but a similar cross-neutralizing antibody against Omicron and T cell responses in the homologous booster group compared to the heterologous booster group. Breakthrough infection in the homologous booster group (n = 11) significantly increased the neutralizing antibody, but T cell responses remained low. Our data may impact government public health policy regarding the administration of mix-and-match vaccines, where both vaccination regimes can be employed should there be shortages of certain vaccines.

Safety of heterologous ChAdOx1-S/BNT162b2 primary schedule versus homologous BNT162b2 vaccination: Insights from an Italian post-marketing study, 2021.

During COVID-19 vaccination campaign, possible ChAdOx1-S-associated risks of thrombosis with thrombocytopenia syndrome led to implement ChAdOx1-S/BNT162b2 heterologous vaccination, despite the limited information on its reactogenicity and safety. We conducted a prospective observational post-marketing surveillance study to assess the safety of this heterologous schedule. A casually selected sample of recipients (n: 85; age: 18-60 years) of ChAdOx1-S/BNT162b2 at the vaccination hub of the Foggia Hospital, Italy, was matched with an equal sample of recipients of homologous BNT162b2. Safety was evaluated 7 days, 1 month and 14 weeks after the primary vaccination series using an adapted version of the "V-safe active surveillance for COVID-19 vaccine safety" CDC standardized questionnaire. After 7 days, local reactions were highly frequent (>80%) in both groups, and systemic reactions were less common (<70%). Moderate or severe pain at the injection site (OR = 3.62; 95%CI, 1.45-9.33), moderate/severe fatigue (OR = 3.40; 95%CI, 1.22-9.49), moderate/severe headache (OR = 4.72; 95%CI, 1.37-16.23), intake of antipyretics (OR = 3.05; 95 CI%, 1.35-6.88), inability to perform daily activities and work (OR = 2.64; 95%CI, 1.24-5.62) were significantly more common with heterologous than homologous vaccination. No significant difference in self-reported health status was recorded 1 month or 14 weeks after the second dose with BNT162b2 or ChAdOx1-S/BNT162b2. Our study confirms the safety of both heterologous and homologous vaccination, with a slight increase in some short-term adverse events for the heterologous regimen. Therefore, administering a second dose of a mRNA vaccine to the recipients of a previous dose of viral vector vaccine may have represented an advantageous strategy to improve flexibility and to accelerate the vaccination campaign.

Remitting Seronegative Symmetrical Synovitis with Pitting Oedema Following Administration of the Chadox1-S/NCOV-19 Coronavirus Vaccine.

Introduction: We describe a case of remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome following administration of the ChAdOx1-S/nCoV-19 [recombinant] vaccine, suggesting a possible causal link. Case Description: A 72-year-old man presented to his general practitioner with swollen, oedematous hands and legs 2 weeks after receiving a coronavirus vaccine. He had raised inflammatory markers but remained systemically well. He was initially presumed to have cellulitis, but his symptoms persisted despite several courses of antibiotics. Deep vein thromboses, cardiac failure, renal failure and hypoalbuminaemia were ruled out. Upon Rheumatology review, he was diagnosed as having RS3PE syndrome with the Covid vaccine suspected of being an immunogenic trigger. Following initiation of steroid therapy, his symptoms improved dramatically, as is characteristic of RS3PE syndrome. Discussion: The pathophysiology of RS3PE is unclear. It is known to have various triggers and associations including infections, certain vaccines and malignancy. This case highlights that a coronavirus vaccine (ChAdOx1-S/nCoV-19 [recombinant] vaccine) is also a possible trigger. Factors that make the diagnosis likely include an acute onset of symptoms including pitting oedema in a typical distribution, age above 50, and unremarkable autoimmune serology. Other learning points from this case include the importance of antibiotic stewardship and the need to explore non-infectious causes of illness when antibiotics do not improve symptoms. Conclusion: The ChAdOx1-S/nCoV-19 [recombinant] vaccine is a possible trigger of RS3PE. However, the benefits of vaccines against coronavirus outweigh the risks in the majority of patients. LEARNING POINTS: This case demonstrates a possible link between the ChAdOx1-S/nCoV-19 [recombinant] vaccine and autoimmune conditions such as RS3PE.It is important to consider alternative diagnoses when antibiotic regimes fail to work.A barrier to accurate diagnosis includes an episodic approach, where a patient presents to multiple clinicians acutely rather than having a long-term, continuous relationship with a single multi-disciplinary team, where response to treatment can be monitored.

Thrombosis with thrombocytopenia syndrome (TTS) following adenovirus vector COVID-19 vaccination in Canada.

INTRODUCTION: Identifying and monitoring adverse events following vaccination contributed to the safety and effectiveness of COVID-19 mass vaccination campaigns. In March 2021, international reports emerged of an adverse event following vaccination with adenovirus vector COVID-19 vaccines (ChAdOx1-S [recombinant] and Ad26.COV2.S) of thrombosis with low platelet counts, referred to as thrombosis with thrombocytopenia syndrome (TTS). We described TTS reports in Canada following adenovirus vector COVID-19 vaccines and investigated whether the observed number of events were higher than expected. METHODS: Reports of TTS following receipt of ChAdOx1-S [recombinant] or Ad26.COV2.S meeting the Canadian case definition for TTS and diagnostic certainty levels 1-3 of the Brighton Collaboration case definition, submitted to the Canadian Adverse Events Following Immunization Surveillance System and Canada Vigilance Database between February 26, 2021 and October 31, 2022 were included. Demographics and characteristics of the TTS reports are described along with an analysis comparing the observed number of reports to the expected number. RESULTS: As of October 31, 2022, 56 reports of TTS following administration of ChAdOx1-S [recombinant] and no reports following Ad26.COV2.S vaccines were reported in Canada, of which 37 had functionally positive anti-PF4 antibodies. The median age was 56 years; males accounted for 54 % of reports. Five deaths were reported. The observed number of reports exceeded the expected for all ages and sexes combined, as well as for males aged 30-49 and 60-69 years, and females aged 40-59 years. CONCLUSION: Based on international surveillance data, Canada evaluated a statistical signal of TTS following adenovirus vector vaccines. The investigation of this signal demonstrated how post-market vaccine safety surveillance systems were successful in investigating rare adverse events during the rollout of COVID-19 vaccines in Canada. As adenovirus vector vaccines continue to be administered, characterization of the association between the vaccine and TTS informs immunization programs and policies.