Expert Review of Global Real-World Data on COVID-19 Vaccine Booster Effectiveness & Safety During the Omicron-dominant Phase of the Pandemic (preprint)

Introduction COVID-19 vaccines have been highly effective in reducing morbidity and mortality during the pandemic. However, the emergence of the Omicron (B.1.1.529) variant and subvariants as the globally dominant strains have raised doubts about the effectiveness of currently-available vaccines and prompted debate about potential future vaccination strategies.Areas covered Using the publicly available IVAC VIEW-hub platform, we reviewed 52 studies on vaccine effectiveness (VE) after booster vaccinations. VE data were reported for SARS-CoV-2 symptomatic infection, severe disease and death and stratified by vaccine schedule and age. In addition, a non-systematic literature review of safety was performed to identify single or multi-country studies investigating adverse event rates for at least two of the currently-available COVID-19 vaccines.Expert opinion Booster shots of the current COVID-19 vaccines provide consistently high protection against Omicron-related severe disease and death. Additionally, this protection appears to be conserved for at least 3 months, with a small but significant waning after that time. The positive risk-benefit ratio of these vaccines is well established, thus increasing confidence in administering additional doses as required. Future vaccination strategies will likely include a combination of schedules based on a person’s risk profile, as overly frequent boosting may be neither beneficial nor sustainable for the general population.

UB-612 Multitope Vaccine Targeting SARS-CoV-2 Spike and Non-Spike Proteins Provides Broad and Durable Immune Responses (preprint)

IRBThe SARS-CoV-2 non-Spike (S) structural protein targets of nucleocapsid (N), membrane (M) and envelope (E), critical in the host cell interferon response and memory T-cell immunity, have been grossly overlooked since the inception of COVID vaccine development. To pursue a universal (pan-sarbecovirus) vaccine against ever-emergent future mutants, we explored booster immunogenicity of UB-612, a multitope-vaccine that contains S1-RBD-sFc protein and sequence-conserved rationally designed promiscuous Th and CTL epitope peptides on the Sarbecovirus N, M and S2 proteins. To a subpopulation of infection-free participants (aged 18-85 years) involved in a two-dose Phase-2 trial, a UB-612 booster (third dose) was administered 6-8 months after the second dose. The immunogenicity was evaluated at 14 days post-booster with overall safety monitored until the end of study. The booster induced high viral-neutralizing antibodies against live Wuhan WT (VNT50, 1,711) and Delta (VNT50, 1,282); and against pseudovirus WT (pVNT50, 11,167) vs. Omicron BA.1/BA.2/BA.5 variants (pVNT50, 2,314/1,890/854), respectively. The lower primary neutralizing antibodies in the elderly were uplifted upon boosting to approximately the same high level in young adults. UB-612 also induced potent, durable Th1-oriented (IFN-{gamma}+-) responses (peak/pre-boost/post-boost SFU/106 PBMCs, 374/261/444) along with robust presence of cytotoxic CD8+ T cells (peak/pre-boost/post-boost CD107a+-Granzyme B+, 3.6%/1.8%/1.8%). Booster vaccination is safe and well tolerated without SAEs. By recognition against epitopes on Spike (S1-RBD and S2) and non-Spike (N and M) structure proteins, UB-612 provides potent, broad and long-lasting B-cell and T-cell memory immunity and offers a potential as a universal vaccine to fend off Omicrons and new VoCs.

UB-612, a Multitope Universal Vaccine Eliciting a Balanced B and T Cell Immunity against SARS-CoV-2 Variants of Concern (preprint)

Importance. The SARS-CoV-2 non-spike structural proteins of nucleocapsid (N), membrane (M) and envelope (E) are critical in the host cell interferon response and memory T-cell immunity and have been grossly overlooked in the development of COVID vaccines. Objective. To determine the safety and immunogenicity of UB-612, a multitope vaccine containing S1-RBD-sFc protein and rationally-designed promiscuous peptides representing sequence-conserved Th and CTL epitopes on the Sarbecovirus nucleocapsid (N), membrane (M) and spike (S2) proteins. Design, setting and participants. UB-612 booster vaccination was conducted in Taiwan. A UB-612 booster dose was administered 6-8 months post-2nd dose in 1,478 vaccinees from 3,844 healthy participants (aged 18-85 years) who completed a prior placebo (saline)-controlled, randomized, observer-blind, multi-center Phase-2 primary 2-dose series (100-ug per dose; 28-day apart) of UB-612. The interim safety and immunogenicity were evaluated until 14 days post-booster. Exposure. Vaccination with a booster 3rd-dose (100-ug) of UB-612 vaccine. Main outcomes and measures. Solicited local and systemic AEs were recorded for seven days in the e-diaries of study participants, while skin allergic reactions were recorded for fourteen days. The primary immunogenicity endpoints included viral-neutralizing antibodies against live SARS-CoV-2 wild-type (WT, Wuhan strain) and live Delta variant (VNT50), and against pseudovirus WT and Omicron variant (pVNT50). The secondary immunogenicity endpoints included anti-S1-RBD IgG antibody, S1-RBD:ACE2 binding inhibition, and T-cell responses by ELISpot and Intracellular Staining. Results. No post-booster vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. The UB-612 booster prompted a striking upsurge of neutralizing antibodies against live WT Wuhan strain (VNT50, 1,711) associated with unusually high cross-neutralization against Delta variant (VNT50, 1,282); and similarly with a strong effect against pseudovirus WT (pVNT50, 6,245) and Omicron variant (pVNT50, 1,196). Upon boosting, the lower VNT50 and pVNT50 titers of the elderly in the primary series were uplifted to the same levels as those of the young adults. The UB-612 also induced robust, durable VoC antigen-specific Th1-oriented (IFN-{gamma}+-) responses along with CD8+ T-cell (CD107a+-Granzyme B+) cytotoxicity. Conclusions and relevance. With a pronounced cross-reactive booster effect on B- and T-cell immunity, UB-612 may serve as a universal vaccine booster for comprehensive immunity enhancement against emergent VoCs. Trial registration. [ClinicalTrials.gov: NCT04773067]

Expert Review of Global Real-World Vaccine Effectiveness Against SARS-CoV-2 (preprint)

IntroductionCOVID-19 vaccines have been highly effective in reducing morbidity and mortality during the pandemic. While primary series vaccination rates are generally high in Southeast Asian (SEA) countries, various factors have limited the rollout and impact of booster doses.Areas coveredWe reviewed 79 studies in the publicly available International Vaccine Access Center (IVAC) VIEW-hub platform on vaccine effectiveness (VE) after primary immunizations with two-dose schedules. VE data were reported for SARS-CoV-2 infection, COVID-19-related hospitalizations and deaths, and stratified across variants of concern (VOC), age, study design and prior SARS-CoV-2 infection for mRNA vaccines (BNT162b2, mRNA-1273 and combinations of both), vector vaccines (AstraZeneca, AZD1222 “Vaxzevria”) and inactivated virus vaccines (CoronaVac).Expert opinionThe most-studied COVID-19 vaccines provide consistently high (>90%) protection against serious clinical outcomes like hospitalizations and deaths, regardless of variant. Additionally, this protection appears equivalent for mRNA vaccines and vector vaccines like AZD1222, as supported by our analysis of local Asian and relevant international data, and by insights from SEA experts. Given the continued impact of COVID-19 hospitalizations and deaths on healthcare systems worldwide, encouraging vaccination strategies that can reduce this burden is more relevant than attempting to prevent broader but milder infections with specific variants, including Omicron.Article highlights - VE was high and comparable for both AZD1222 and mRNA vaccine types (91%-93%) in protecting against hospitalization and death from COVID-19, regardless of age.- VE against symptomatic infections trended higher (though not significantly) for mRNA-based vaccines compared to AZD1222.- Waning of VE since time of vaccination was observed for symptomatic infections but was limited for serious COVID-19 outcomes. A sub-analysis of studies with comparative arms evaluating the VE of different vaccines in the same settings also confirmed these observations for all VOC assessed, with all vaccines conferring a high level of protection against serious outcomes.- For Omicron, there is limited comparative data within the IVAC dataset, however, expert review of emerging data suggests that VE against all outcomes is lower for all COVID-19 vaccines, than for the Delta variant.- Data from the UK indicate that VE improves with a booster dose and that VE continues to be very similar, irrespective of the type of vaccine used.- Importantly, all COVID-19 vaccines evaluated here have favorable benefit/risk profiles.- Although many SEA countries have high rates of primary vaccination, there are still challenges to achieving high booster dose coverage. The results of this analysis suggest that the most effective way to achieve vaccine booster targets, particularly in resource-limited settings, would simply be to consider any vaccines which have good safety and comparable effectiveness profiles, particularly against severe outcomes, and that are accessible and optimal for the local situation.- This review reinforces the value of real-world evidence to support efforts advocating for the completion of primary series and booster vaccinations where appropriate, especially to restore VE against emerging VOC such as Omicron. However, data gaps still persist, given the lag between the emergence of new variants, updated vaccine schedules and VE data to inform their impact. 

Potent Anti-Delta Effect By a Booster Third-Dose of UB-612, a Precision-Designed SARS-CoV-2 Multitope Protein-Peptide Vaccine (preprint)

SARS-CoV-2 breakthrough infection occurs due to waning immunity time-to-vaccine, to which the globally-dominant, highly-contagious Delta variant is behind the scene. In the primary 2-dose and booster series of clinical Phase-1 trial, UB-612 vaccine, which contains S1-RBD and synthetic Th/CTL peptide pool for activation of humoral and T-cell immunity, induces substantial, prolonged viral-neutralizing antibodies that goes parallel with a long-lasting T-cell immunity; and a booster (3rd ) dose can prompt recall of memory immunity to induce profound, striking antibodies with the highest level of 50% viral-neutralizing GMT titers against live Delta variant reported for any vaccine. The unique design of S1-RBD only plus multitope T-cell peptides may have underpinned UB-612’s potent anti-Delta effect, while the other full S protein-based vaccines are affected additionally by mutations in the N-terminal domain sequence which contains additional neutralizing epitopes. UB-612, safe and well-tolerated, could be effective for boosting other vaccine platforms that have shown modest homologous boosting. [Funded by United Biomedical Inc., Asia; ClinicalTrials.gov ID: NCT04967742 and NCT04545749]

Safety and Immunogenicity of CpG 1018 and Aluminium Hydroxide-Adjuvanted SARS-CoV-2 S-2P Protein Vaccine MVC-COV1901: A Large-Scale Double-Blinded, Randomised, Placebo-Controlled Phase 2 Trial (preprint)

BackgroundWe have assessed the safety and immunogenicity of the COVID-19 vaccine MVC-COV1901, a recombinant protein vaccine containing prefusion-stabilized spike protein S-2P adjuvanted with CpG 1018 and aluminium hydroxide. MethodsThis is a phase 2, prospective, randomised, double-blind, placebo-controlled, and multi-centre study to evaluate the safety, tolerability, and immunogenicity of the SARS-CoV-2 vaccine candidate MVC-COV1901. The study comprised 3,844 participants of [≥] 20 years who were generally healthy or with stable pre-existing medical conditions. The study participants were randomly assigned in a 6:1 ratio to receive either MVC-COV1901 containing 15 g of S-2P protein or placebo containing saline. Participants received two doses of MVC-COV1901 or placebo, administered 28 days apart via intramuscular injection. The primary outcomes were to evaluate the safety, tolerability, and immunogenicity of MVC-COV1901 from Day 1 (the day of first vaccination) to Day 57 (28 days after the second dose). Immunogenicity of MVC-COV1901 was assessed through geometric mean titres (GMT) and seroconversion rates (SCR) of neutralising antibody and antigen-specific immunoglobulin. This clinical trial is registered at ClinicalTrials.gov: NCT04695652. FindingsFrom the start of this phase 2 trial to the time of interim analysis, no vaccine-related Serious Adverse Events (SAEs) were recorded. The most common solicited adverse events across all study participants were pain at the injection site (64%), and malaise/fatigue (35%). Fever was rarely reported (<1%). For all participants in the MVC-COV1901 group, at 28 days after the second dose against wild type SARS-CoV-2 virus, the GMT was 662{middle dot}3 (408 IU/mL), the GMT ratio was 163{middle dot}2, and the seroconversion rate was 99{middle dot}8%. InterpretationMVC-COV1901 shows good safety profiles and promising immunogenicity responses. The current data supports MVC-COV1901 to enter phase 3 efficacy trials and could enable regulatory considerations for Emergency Use Authorisation (EUA). FundingMedigen Vaccine Biologics Corporation and Taiwan Centres for Disease Control.

Changes in Emergency Department Responses Between SARS and COVID-19 in Taiwan (preprint)

Background: After SARS outbreak, infectious control polices had been reformed in Taiwan, but there was no evidence to prove its effectiveness. This study compared emergency department (ED) responses to the SARS and COVID-19 epidemics and investigate how policy changes affect infection prevention.Methods: A 2003 questionnaire regarding the responses of EDs to SARS was resent to EDs during the COVID-19 epidemic in 2020. The use of personal protective equipment (PPE), implementation of infection control measures (ICMs), and difficulties in performance were compared. Data collection included hospital level, different PPE types provided and ICMs implemented, timing for using PPE and ICMs, and a difficulty rating scale for ICM implementation.Results: In total, 100 EDs responded to the questionnaire in 2003 was reviewed and compared with 131 EDs in 2020. In COVID-19 epidemic, the use of basic PPEs and ICMs was mostly significantly improved, but the percentage of preparedness in high grade PPEs was still low. Quarantine of fever patients outside of EDs was less performed in small to medium sized hospitals (p=0.008 and 0.004). All of the additional ICMs were significantly less implemented in local hospitals. The timing to use PPE and implement ICMs were simultaneously and significantly performed at early stage. Instituting a fever triage ward and restricting fever patient admission became less necessary. The closure of EDs remained the most difficult to perform in both outbreaks. Conclusion: After the policy reforms, ED responses became earlier and more consistent. However, inadequate quarantine resources at EDs in low- and middle-grade hospitals may lead to breaches in future epidemics.