Profiling Humoral Immunity After Mixing and Matching COVID-19 Vaccines Using SARS-CoV-2 Variant Protein Microarrays.

In November 2022, 68% of the population received at least one dose of COVID-19 vaccines. Owing to the ongoing mutations, especially for the variants of concern (VOCs), it is important to monitor the humoral immune responses after different vaccination strategies. In this study, we developed a SARS-CoV-2 variant protein microarray that contained the spike proteins from the VOCs, e.g., alpha, beta, gamma, delta, and omicron, to quantify the binding antibody and surrogate neutralizing antibody. Plasmas were collected after two doses of matching AZD1222 (AZx2), two doses of matching mRNA-1273 (Mx2), or mixing AZD1222 and mRNA-1273 (AZ+M). The results showed a significant decrease of surrogate neutralizing antibodies against the receptor-binding domain in all VOCs in AZx2 and Mx2 but not AZ+M. A similar but minor reduction pattern of surrogate neutralizing antibodies against the extracellular domain was observed. While Mx2 exhibited a higher surrogate neutralizing level against all VOCs compared with AZx2, AZ+M showed an even higher surrogate neutralizing level in gamma and omicron compared with Mx2. It is worth noting that the binding antibody displayed a low correlation to the surrogate neutralizing antibody (R-square 0.130-0.382). This study delivers insights into humoral immunities, SARS-CoV-2 mutations, and mixing and matching vaccine strategies, which may provide a more effective vaccine strategy especially in preventing omicron.

Perception and Acceptance of Using Different Generic Types of COVID-19 Vaccine, the "Mix-and-Match" Strategy, in Saudi Arabia: Cross-Sectional Web-Based Survey.

Background: Soon after the COVID-19 pandemic was declared, a pharmaceutical company expressed rapid interest in developing a safe and effective vaccine candidate to contain the spread of SARS-CoV-2 infections. The FDA approved the Pfizer-BioNTech, AstraZeneca, Moderna, and Janssen vaccines. Here, we investigated the attitude and acceptance of using different generic types of COVID-19 vaccines in Saudi Arabia. Methods: This study is a cross-sectional study using an online survey conducted in Saudi Arabia from the 19th of October to the 6th of December 2021. The questionnaire was distributed using social media platforms such as Twitter, WhatsApp, and Facebook. The inclusion criteria to participate in this study were adults who live in Saudi Arabia (Saudis or non-Saudis) and had two doses of COVID-19 vaccinations. Result: 3486 participants were included in this study, and 67.5% of the participants had side effects after the first dose. Similarly, 66.7% of the study participants had side effects after administering the second dose. Our data showed that most participants were unsure if the heterologous COVID-19 vaccination could cause severe side effects. In addition, 47.6% of the participants refused to receive a different generic type of COVID-19 vaccine due to fear of health problems. However, most participants obtained information regarding COVID-19 vaccination from the Saudi Ministry of Health. Conclusions: We found a low level of acceptance for receiving different generic types of vaccines if the participants had a choice. Therefore, plans should focus on increasing the acceptance level among the Saudi population through official platforms such as the Saudi Ministry of Health and private clinics.

'Mix and Match' vaccination: Is dengue next?

The severity of the COVID-19 pandemic and the development of multiple SARS-CoV-2 vaccines expedited vaccine 'mix and match' trials in humans and demonstrated the benefits of mixing vaccines that vary in formulation, strength, and immunogenicity. Heterologous sequential vaccination may be an effective approach for protecting against dengue, as this strategy would mimic the natural route to broad dengue protection and may overcome the imbalances in efficacy of the individual leading live attenuated dengue vaccines. Here we review 'mix and match' vaccination trials against SARS-CoV-2, HIV, and dengue virus and discuss the possible advantages and concerns of future heterologous immunization with the leading dengue vaccines. COVID-19 trials suggest that priming with a vaccine that induces strong cellular responses, such as an adenoviral vectored product, followed by heterologous boost may optimize T cell immunity. Moreover, heterologous vaccination may induce superior humoral immunity compared to homologous vaccination when the priming vaccine induces a narrower response than the boost. The HIV trials reported that heterologous vaccination was associated with broadened antigen responses and that the sequence of the vaccines significantly impacts the regimen's immunogenicity and efficacy. In heterologous dengue immunization trials, where at least one dose was with a live attenuated vaccine, all reported equivalent or increased immunogenicity compared to homologous boost, although one study reported increased reactogenicity. The three leading dengue vaccines have been evaluated for safety and efficacy in thousands of study participants but not in combination in heterologous dengue vaccine trials. Various heterologous regimens including different combinations and sequences should be trialed to optimize cellular and humoral immunity and the breadth of the response while limiting reactogenicity. A blossoming field dedicated to more accurate correlates of protection and enhancement will help confirm the safety and efficacy of these strategies.

Humoral and Cellular Immune Responses to Vector, Mix-and-Match, or mRNA Vaccines against SARS-CoV-2 and the Relationship between the Two Immune Responses.

We investigated how differences in age, sex, or vaccine type can affect humoral and cellular immune responses after vaccination with vector (ChAdOx1 nCoV-19), mix-and-match (first, ChAdOx1 nCoV-19, and second, BNT162b2), or mRNA (BNT162b2 or mRNA-1273) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Venous blood was collected from 573 subjects (vector, 396; mix-and-match, 96; and mRNA, 81) before the first vaccination (T0), 7 to 8 weeks (vector) or 3 to 4 weeks (mRNA) after the first vaccination (T1), and 3 to 4 weeks after the second vaccination (T2). The humoral and cellular immune responses were evaluated using Elecsys anti-SARS-CoV-2 (Roche), Alinity SARS-CoV-2 IgG II Quant (Abbott), cPass SARS-CoV-2 neutralization antibody detection (GenScript), and QuantiFERON SARS-CoV-2 (Qiagen) kits. At T1, the levels of the receptor-binding domain antibodies (RBD Ab) and neutralizing antibodies (NAb) decreased with aging, but interferon gamma release (IGR) levels increased. The RBD Ab, NAb, and IGR levels were higher in females than in males at T1 and T2. The NAb levels were higher in the mix-and-match and mRNA vaccine groups than in the vector vaccine group at T2. The RBD Ab and IGR levels were higher in the mRNA vaccine group than in the vector or mix-and-match vaccine groups at T2. The optimal cutoffs for RBD Ab and NAb, which were used to determine the presence of T cell responses, were 5.7 binding antibody units per milliliter (BAU mL-1) and 12.0 IU mL-1, respectively. Age, sex, and vaccine type affected the humoral and cellular immune responses, and T cell responses could be estimated from RBD Ab and NAb levels. IMPORTANCE There have been few studies that comprehensively evaluated factors affecting immune responses and the correlation between humoral and cellular immune responses after vector, mix-and-match, and mRNA vaccines against SARS-CoV-2. Therefore, we analyzed the effects of age, sex, and the different vaccine regimens on the immune responses to vaccination against SARS-CoV-2. The correlation between humoral and cellular immune responses and the cutoffs were derived for RBD antibodies and neutralizing antibodies to predict the presence of the cellular immune responses. In this comprehensive study, we demonstrated that there were differences in the immune responses induced after vaccination depending on the age and sex of an individual. Among the three vaccine regimens, the mix-and-match and mRNA vaccines induced the most robust immune responses. Finally, the proposed optimal cutoffs for RBD and neutralizing antibodies may be useful for predicting cellular immune responses when assays for cellular immune responses are not available.

Risk Factors and Incidence Rates of Self-Reported Short-Term Adverse Events of COVID-19 Vaccine Booster Dose.

With the spread of the new SARS-CoV-2 variants, many countries have begun COVID-19 vaccine booster programs with the mix-and-match strategy. However, research on the adverse events (AE) of booster doses is still scarce. The aim of our study was to analyze the reported incidence rate (IR), and factors associated with AE, including short-term serious adverse events (SAE) and short-term non-serious adverse events (NSAE), among different vaccine products through the hospital-based Vaccine Adverse Event Reporting System (VAERS). A total of 7432 records were collected during the three-month study period. While more than half of the responses (52.2%) reported the presence of AE after receiving a booster dose, only a few AE were considered SAE (2.4%). AE were significantly higher among women and people of younger age, and the brand of vaccines is the strongest factor associated with post-booster dose AE. The incidence of AE in mRNA1273 is higher than in BNT162b2 and MVC-COV1901 (IRR mRNA1273 vs. BNT162b2: 1.22, 95% CI: 1.11-1.34; BNT162b2 vs. MVC-COV1901: 2.77, 95% CI: 2.27-3.39). The IR of different groups were calculated to support the decision making of the booster vaccine. Although AE were not uncommon for booster vaccines, almost all AE were not serious and predictable using estimated IR. This result can be used to optimize booster vaccine decision making.

Mix-and-Match COVID-19 Vaccinations (Heterologous Boost): A Review.

Various safe and effective COVID-19 vaccines utilizing different platforms (mRNA, adenovirus vector, inactivated virus-based) are available against SARS-CoV-2 infection. A prime-boost regimen (administration of two doses) is recommended to induce an adequate and sustained immune response. Most of these vaccines follow a homologous regimen (the same type of vaccine as priming and booster doses). However, there is a growing interest in a heterologous prime-boost vaccination regimen to potentially help address concerns posed by fluctuating vaccine supplies, serious adverse effects (anaphylaxis and thromboembolic episodes following adenovirus-based vaccines), new emerging virulent strains, inadequate immune response in immunocompromised individuals, and waning immunity. Various studies have demonstrated that heterologous prime-boost vaccination may induce comparable or higher antibody (spike protein) titers and a similar reactogenicity profile to the homologous prime-boost regimen. Based on these considerations, the Center for Disease Control and Prevention has issued guidance supporting the "mix-and-match" heterologous boost COVID-19 vaccine strategy.

Immunogenicity and Reactogenicity of the Booster Dose of COVID-19 Vaccines and Related Factors: A Panel Study from the General Population in Serbia.

The Republic of Serbia applied the booster dose of the following COVID-19 vaccines: BNT162b2 mRNA (Pfizer-BioNTech), Sinopharm BBIBP-CorV (Vero Cell®), Gam-COVID-Vac (Sputnik V) and ChAdOk1 nCoV-19 (AstraZeneca). We aimed to examine the immunogenicity and reactogenicity of the booster dose and identify factors related to immune response and adverse events. Panel study, conducted during August and September 2021, included 300 persons receiving the booster dose at the Institute of Public Health of Serbia. Blood samples were taken on the day of receiving the booster dose, and after 7 and 28 days. When applying homologous regimen, the average increase in anti-spike immunoglobulin G was 8782.2 (after 7 days), 1213.9 after 28 days, while 9179.5 (after 7 days) and 16,728.1 after 28 days of heterologous regimen. Sinopharm BBIBP-CorV (p < 0.001) and Sputnik V (p < 0.001), age 65 and over (p = 0.001) and currently smoking (p < 0.001) were independently associated with lower levels of anti-spike immunoglobulin G. Female sex (OR = 1.77; 95%CI = 1.01-3.12), previous COVID-19 infection (OR = 3.62; 95%CI = 1.13-11.63) and adverse events after the second dose (OR = 2.66; 95%CI = 1.33-5.32) were independently associated with intense systemic adverse events 7 days after. Booster dose significantly increased antibodies titers, especially 28 days after heterologous regimen, without a significant increase in reactogenicity.

Human Milk Antibody Response After Combining Two Different COVID-19 Vaccines: Mix-and-Match.

BACKGROUND: SARS-CoV-2-specific antibodies are secreted into human milk after women are vaccinated against COVID-19, which might protect the breastfed infant. Due to several reports of severe side-effects of the Oxford-AstraZeneca ChAdOx1 (AZD1222) vaccine against COVID-19, some lactating women followed a heterologous vaccination schedule consisting of the first dose of AZD1222 and a second dose of an mRNA-based vaccine. However, it is unclear whether this generates a significant SARS-CoV-2-specific antibody response in human milk. MAIN ISSUE: To quantify the SARS-CoV-2-specific antibody response in human milk of two lactating women receiving a heterologous vaccination schedules: AZD1222 and mRNA-based vaccine (Pfizer-BioNTech [BNT162b2] and Moderna [mRNA-1273]). MANAGEMENT: Both participants collected 16 samples of human milk longitudinally. SARS-CoV-2-specific Immunoglobulin A was measured using an enzyme-linked immunosorbent assay. CONCLUSION: Based on our results, it could be suggested that heterologous vaccination with AZD1222 and an mRNA-based vaccine can elicit a significant SARS-CoV-2 specific IgA response in human milk.

Immunogenicity of COVID-19 Vaccination in Patients With End-Stage Renal Disease Undergoing Maintenance Hemodialysis: The Efficacy of a Mix-and-Match Strategy.

BACKGROUND: The objective of this study was to evaluate the immunogenicity of coronavirus disease 2019 (COVID-19) vaccination in patients with end-stage renal disease (ESRD) on hemodialysis. METHODS: ESRD patients at the hemodialysis center of a tertiary-care university-affiliated hospital and healthy employees at the clinical laboratory center were prospectively recruited between March and June 2021. For severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody analysis, blood samples were collected serially on days 0, 14, 28, and 56 after the first vaccine dose, and on days 7 and 50 after the second dose. Antibodies against the SARS-CoV-2 spike protein were quantified, and SARS-CoV-2 neutralizing antibodies were measured in the serum and plasma. RESULTS: Thirty-one ESRD patients and 55 healthy employees were regularly monitored. Twenty-five (80.6%) ESRD patients on hemodialysis received a mix-and-match strategy with ChAdOx1-BNT162b2 (AZ-Pf group) and six (19.4%) received two doses of ChAdOx1 (AZ-AZ group). ESRD patients on hemodialysis showed lower binding antibody titers and neutralizing antibody activities compared to healthy participants following the first vaccination with ChAdOx1. After the second dose, AZ-Pf group had higher immunogenicity than healthy people on days 7 and 50. The binding antibody titer and neutralizing antibody activities on days 7 and 50 were significantly higher in the AZ-Pf group than in the AZ-AZ group. CONCLUSION: ESRD patients on hemodialysis receiving the mix-and-match strategy (ChAdOx1-BNT162b2) have COVID-19 vaccine immunogenicity comparable to healthy individuals receiving two doses of ChAdOx1. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04871945.

Revival of the heterologous prime-boost technique in COVID-19: An outlook from the history of outbreaks.

BACKGROUND: The heterologous prime-boost vaccination technique is not novel as it has a history of deployment in previous outbreaks. AIM: Hence, this narrative review aims to provide critical insight for reviving the heterologous prime-boost immunization strategy for SARS-CoV-2 vaccination relative to a brief positive outlook on the mix-dose approach deployed in previous and existing outbreaks (ie, Ebola virus disease (EVD), malaria, tuberculosis, hepatitis B, HIV and influenza virus). METHODOLOGY AND MATERIALS: A Boolean search was carried out to find the literature in MEDLINE-PubMed, Clinicaltrials, and Cochrane Central Register of Controlled Trials databases up till December 22, 2021, using the specific keywords that include "SARS-CoV2", "COVID-19", "Ebola," "Malaria," "Tuberculosis," "Human Immunodeficiency Virus," "Hepatitis B," "Influenza," "Mix and match," "Heterologous prime-boost," with interposition of "OR" and "AND." Full text of all the related articles in English language with supplementary appendix was retrieved. In addition, the full text of relevant cross-references was also retrieved. RESULTS: Therefore, as generally evident by the primary outcomes, that is, safety, reactogenicity, and immunogenicity reported and updated by preclinical and clinical studies for addressing previous and existing outbreaks so far, including COVID-19, it is understood that heterologous prime-boost immunization has been proven successful for eliciting a more efficacious immune response as of yet in comparison to the traditional homologous prime-boost immunization regimen. DISCUSSION: Accordingly, with increasing cases of COVID-19, many countries such as Germany, Pakistan, Canada, Thailand, and the United Kingdom have started administering the heterologous vaccination as the technique aids to rationalize the usage of the available vaccines to aid in the global race to vaccinate majority to curb the spread of COVID-19 efficiently. However, the article emphasizes the need for more large controlled trials considering demographic details of vaccine recipients, which would play an essential role in clearing the mistrust about safety concerns to pace up the acceptance of the technique across the globe. CONCLUSION: Consequently, by combatting the back-to-back waves of COVID-19 and other challenging variants of concerns, including Omicron, the discussed approach can also help in addressing the expected evolution of priority outbreaks as coined by WHO, that is, "Disease X" in 2018 with competency, which according to WHO can turn into the "next pandemic" or the "next public health emergency," thus would eventually lead to eradicating the risk of "population crisis."

Heterologous COVID-19 Vaccination in Spain: A Case Study of Individual Autonomy in the Real World.

In Spain, 1.5 million essential < 60-year-old workers were vaccinated with a first AstraZeneca vaccine dose. After assessing the cases of thrombosis with thrombocytopenia associated to this vaccine, the European Medicines Agency (EMA) supported the administration of 2 doses of the AstraZeneca vaccine with no age restrictions. Nevertheless, Spain decided not to administer the second dose of this vaccine to < 60-year-olds. The government sponsored a clinical trial (CombiVacS) to assess the immunogenicity response to a Pfizer/BioNTech vaccine dose in adults primed with the AstraZeneca vaccine. The positive results backed the Public Health Commission and the Spanish Ministry of Health to offer the Pfizer/BioNTech vaccine as the booster. Nevertheless, regional public health authorities-responsible for administering vaccines-believed that, following the EMA's decision, an AstraZeneca booster dose should be given. The public confrontation of these 2 positions forced the Spanish Health Ministry to request the signature of an informed consent form to those individuals willing to receive the AstraZeneca vaccine booster and rejecting the Pfizer/BioNTech vaccine dose. Eventually, it was decided that these essential workers could choose the vaccine but signing an informed consent form. All relevant information was posted on the Ministry of Health and regional health authorities' websites and provided to potential vaccine recipients at vaccination sites. Most individuals (≥ 75%) chose the AstraZeneca vaccine: perhaps because they likely trusted the EMA more than the CombiVacS results. This unprecedented and massive exercise of individual autonomy about the choice of COVID-19 vaccines from 2 different platforms has shown that adequately informed persons can autonomously weigh their options, regardless of government decisions. Exercising individual autonomy may contribute to the success of future COVID-19 booster vaccination campaigns.

Heterologous prime-boost strategies for COVID-19 vaccines.

BACKGROUND/OBJECTIVE: Heterologous prime-boost doses of COVID-19 vaccines ('mix-and-match' approach) are being studied to test for the effectiveness of Oxford (AZD1222), Pfizer (BNT162b2), Moderna (mRNA-1273) and Novavax (NVX-CoV2373) vaccines for COVID in 'Com-Cov2 trial' in UK, and that of Oxford and Pfizer vaccines in 'CombivacS trial' in Spain. Later, other heterologous combinations of CoronaVac (DB15806), Janssen (JNJ-78436735), CanSino (AD5-nCOV) and other were also being trialled to explore their effectiveness. Previously, such a strategy was deployed for HIV, Ebola virus, malaria, tuberculosis, influenza and hepatitis B to develop the artificial acquired active immunity. The present review explores the science behind such an approach for candidate COVID-19 vaccines developed using 11 different platforms approved by the World Health Organization. METHODS: The candidate vaccines' pharmaceutical parameters (e.g. platforms, number needed to vaccinate and intervals, adjuvanted status, excipients and preservatives added, efficacy and effectiveness, vaccine adverse events, and boosters), and clinical aspects must be analysed for the mix-and-match approach. Results prime-boost trials showed safety, effectiveness, higher systemic reactogenicity, well tolerability with improved immunogenicity, and flexibility profiles for future vaccinations, especially during acute and global shortages, compared to the homologous counterparts. CONCLUSION: Still, large controlled trials are warranted to address challenging variants of concerns including Omicron and other, and to generalize the effectiveness of the approach in regular as well as emergency use during vaccine scarcity.

Efficacy of mRNA, adenoviral vector, and perfusion protein COVID-19 vaccines.

Coronavirus disease 2019 (COVID-19) has a devastating impact on global populations triggered by a highly infectious viral sickness, produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The third major cause of mortality in the United States, following heart disease and cancer in 2020, was undoubtedly COVID-19. The centers for disease control and prevention (CDC) and the world health organization (WHO) separately developed a categorization system for differentiating new strains of SARS-CoV-2 into variants of concern (VoCs) and variants of interest (VoIs) with the continuing development of various strains SARS-CoV-2. By December 2021, five of the SARS-CoV-2 VoCs were discovered from the onset of the pandemic depending on the latest epidemiologic report by the WHO: Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529). Mutations in the receptor-binding domain (RBD) and n-terminal domain (NTD) have been found throughout all five identified VoCs. All strains other than the delta mutant are often found with the N501Y mutation situated on the RBD, resulting in higher binding between the spike protein and angiotensin-converting enzyme 2 (ACE2) receptors, enhanced viral adhesion, and following the entrance to host cells. The introduction of these new strains of SRAS-CoV-2 is likely to overcome the remarkable achievements gained in restricting this viral disease to the point where it is presented with remarkable vaccine developments against COVID-19 and strong worldwide mass immunization initiatives. Throughout this literature review, the effectiveness of current COVID-19 vaccines for managing and prohibiting SARS-CoV-2 strains is thoroughly described.

COVID-19 vaccines mix-and-match: The concept, the efficacy and the doubts.

The search for developing effective vaccines against SARS-CoV-2 began with the start of the COVID-19 pandemic, and the first vaccine dose was administered in December 2020. Today, full vaccination of most of the world's population is considered the most important means to overcome the COVID-19 pandemic. Vaccination has been associated with various struggles. Some adverse reactions have resulted in the discontinuation of the specific vaccines use in some countries. Countries in poor regions have faced difficulties supplying enough vaccine doses, and the emergence of new variants of concern has resulted in reduced effectiveness of available vaccines against COVID-19. The mix-and-match strategy, using heterologous vaccines in the first and second doses, might successfully solve the mentioned struggles. Moreover, this strategy has been associated with higher cellular and humoral immune responses without significantly increasing the adverse reactions. Hence, this strategy can help improve the vaccines' effectiveness, and act as a solution for vaccine shortage in poor regions.