Introducing a New Concept for Value-Driven Acceleration in Biopharma Development

This opinion paper seeks to introduce a disruptive model to accelerate product and process development in the biopharmaceutical industry, especially for vaccines. This model is based on the minimum valuable product and process (MVaP&P), a new concept that allows for adaptation and acceleration, which would enable agility in the way biopharmaceuticals are developed. This article discusses how the MVaP&P approach would make it is possible to discipline and structure biopharmaceutical development to achieve a phase-appropriate and strategy-aligned product in the fastest time possible.Copyright © 2022, UBM Medica Healthcare Publications. All rights reserved.

Response to COVID-19 vaccine is reduced in patients with inflammatory bowel disease, but improved with additional dose.

BACKGROUND: Coronavirus disease 2019 (COVID-19) vaccination is recommended for patients with inflammatory bowel disease (IBD); however, suppressed immune responses have been reported for fully vaccinated patients under immunosuppressive therapy, mainly from Western countries. We prospectively analyzed antibody titers of IBD patients in Asia induced by two-dose and additional dose of messengerRNA COVID-19 vaccine. METHODS: After measuring high-affinity antibody titers, factors associated with antibody titers were identified by multiple regression analyses using the following covariates: sex, age (≥60 or <60 years), disease type (Crohn's disease or ulcerative colitis), vaccine type (BNT162b2 or mRNA-1273), time from second/third vaccination, molecular-targeted agent (anti-tumor necrosis factor [TNF] agents, ustekinumab, vedolizumab, tofacitinib, or no molecular-targeted agents), thiopurine, steroid, and 5-aminosalicylic acid. RESULTS: Among 409 patients analyzed, mean titer was 1316.7 U/mL (SD, 1799.3); 403 (98.5%) were judged to be seropositive (≥0.8 U/mL), and 389 (95.1%) had neutralizing antibodies (≥15 U/mL). After the third vaccination, mean titer raised up to 21 123.8 U/mL (SD, 23 474.5); all 179 were seropositive, and 178 (99.4%) had neutralizing antibodies. In 248 patients with genetic data, there was no difference in mean titer after two/third doses between carriers and non-carriers of HLA-A24 associated with severe disease during COVID-19 infection. A multiple regression analyses using covariates revealed that older age, vaccine type (BNT162b2), time from second/third dose, anti-TNF agent, tofacitinib, and thiopurine were independently associated with lower antibody titers. CONCLUSIONS: Our findings further support the recommendation for COVID-19 vaccination in patients under immunosuppressive therapy, especially additional third dose for patients receiving anti-TNF agents and/or thiopurine or tofacitinib.

COVID-19 booster dose induces robust antibody response in pregnant, lactating, and nonpregnant women.

BACKGROUND: Although emerging data during the SARS-CoV-2 pandemic have demonstrated robust messenger RNA vaccine-induced immunogenicity across populations, including pregnant and lactating individuals, the rapid waning of vaccine-induced immunity and the emergence of variants of concern motivated the use of messenger RNA vaccine booster doses. Whether all populations, including pregnant and lactating individuals, will mount a comparable response to a booster dose is not known. OBJECTIVE: This study aimed to profile the humoral immune response to a COVID-19 messenger RNA booster dose in a cohort of pregnant, lactating, and nonpregnant age-matched women. STUDY DESIGN: This study characterized the antibody response against ancestral Spike and Omicron in a cohort of 31 pregnant, 12 lactating, and 20 nonpregnant age-matched controls who received a BNT162b2 or messenger RNA-1273 booster dose after primary COVID-19 vaccination. In addition, this study examined the vaccine-induced antibody profiles of 15 maternal-to-cord dyads at delivery. RESULTS: Receiving a booster dose during pregnancy resulted in increased immunoglobulin G1 levels against Omicron Spike (postprimary vaccination vs postbooster dose; P=.03). Pregnant and lactating individuals exhibited equivalent Spike-specific total immunoglobulin G1, immunoglobulin M, and immunoglobulin A levels and neutralizing titers against Omicron compared with nonpregnant women. Subtle differences in Fc receptor binding and antibody subclass profiles were observed in the immune response to a booster dose in pregnant vs nonpregnant individuals. The analysis of maternal and cord antibody profiles at delivery demonstrated equivalent total Spike-specific immunoglobulin G1 in maternal and cord blood, yet higher Spike-specific FcγR3a-binding antibodies in the cord relative to maternal blood (P=.002), consistent with the preferential transfer of highly functional immunoglobulin. Spike-specific immunoglobulin G1 levels in the cord were positively correlated with the time elapsed since receiving the booster dose (Spearman R, .574; P=.035). CONCLUSION: Study data suggested that receiving a booster dose during pregnancy induces a robust Spike-specific humoral immune response, including against Omicron. If boosting occurs in the third trimester of pregnancy, higher Spike-specific cord immunoglobulin G1 levels are achieved with greater time elapsed between receiving the booster and delivery. Receiving a booster dose has the potential to augment maternal and neonatal immunity.

Acute pulmonary thromboembolism after messenger RNA vaccination against coronavirus disease 2019: A case report.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is defined as thrombosis after inoculation of adenovirus vector vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). VITT rarely occurs with messenger RNA vaccines, and the use of heparin for VITT is also controversial. A 74-year-old female patient with no risk factors for thrombosis was brought to our hospital after loss of consciousness. Nine days before admission, she had received the third vaccine against SARS-CoV-2 (mRNA1273, Moderna). Immediately after transport, cardiopulmonary arrest occurred, prompting extracorporeal membrane oxygenation (ECMO). Pulmonary angiography showed translucent images of both pulmonary arteries, resulting in the diagnosis of acute pulmonary thromboembolism. Unfractionated heparin was administered, but D-dimer subsequently became negative. Pulmonary thrombosis remained in large volume, indicating that heparin was ineffective. Treatment was shifted to anticoagulant therapy using argatroban, which increased D-dimer level and improved respiratory status. The patient was successfully weaned from ECMO and ventilator. Anti-platelet factor 4 antibody examined after treatment initiation showed negative results; however, VITT was considered as an underlying condition because of the time of onset after vaccination, the ineffectiveness of heparin, and the absence of other causes of thrombosis. In case heparin is not effective, argatroban can be an alternative therapy against thrombosis. Learning objective: During the coronavirus disease 2019 pandemic, treatment with vaccine against severe acute respiratory syndrome coronavirus 2 has been widely performed. Vaccine-induced immune thrombotic thrombocytopenia is the most common thrombosis after adenovirus vector vaccines. However, thrombosis can also occur after messenger RNA vaccination. Though commonly used for thrombosis, heparin may be ineffective. Non-heparin anticoagulants should be considered.

Immunogenicity and safety of third-dose mRNA COVID-19 vaccines in healthy adults previously vaccinated with two doses of the ChAdOx1 vaccine.

BACKGROUND/PURPOSE: The efficacy and safety of coronavirus disease 2019 (COVID-19) booster vaccines remain limited. We investigated the immunogenicity and adverse events of the third dose of mRNA vaccines in healthy adults. METHODS: Volunteers vaccinated with two doses of the adenoviral vaccine (ChAdOx1) 12 weeks before were administered with an mRNA COVID-19 vaccine. These were divided into three groups, full-dose mRNA-1273 (group 1); half-dose mRNA-1273 (group 2); and full-dose BNT-162b2 (group 3). Primary outcomes included serum anti-SARS-CoV-2 spike immunoglobulin G (IgG) titers and neutralizing antibody titers against B.1.1.7 (alpha), B.1.617.2 (delta), and B.1.1.529 (omicron) variants. Secondary outcomes included the evaluation of humoral and cellular immunity and vaccine-associated adverse events after the boost. RESULTS: Totally 300 participants were recruited, and 298 participants were enrolled. For all three groups, an increase in anti-SARS-CoV-2 spike IgG geometric mean titers (30.12- to 71.80-fold) and neutralizing antibody titers against the alpha variant (69.80- to 173.23-folds), delta variant (132.69- to 324.63-folds), and omicron variant (135.36- to 222.37-folds) were observed on day 28. All groups showed robust T- and B-cell responses after boosting. Adverse events were overall mild and transient but with higher prevalence and severity in group 1 participants than in other groups. CONCLUSIONS: Third dose mRNA COVID-19 vaccines markedly enhanced cellular and humoral responses and were safe. Immunological responses and adverse events were higher in individuals receiving the full-dose mRNA-1273 vaccine, followed by a half-dose mRNA-1273 vaccine and BNT-162b2 vaccine.

Serological response and safety of heterologous ChAdOx1-nCoV-19/mRNA-1273 prime-boost vaccination with a twelve-week interval.

The appropriate interval between heterologous prime adenoviral vectored vaccination and boost mRNA vaccination remains unclear. We recruited 100 adult participants to receive a prime adenoviral vectored vaccine (ChAdOx1, AstraZeneca) and a boost mRNA vaccine (mRNA-1273, Moderna) 12 weeks apart and checked their serum SARS-CoV-2 anti-spike IgG titers and neutralizing antibody titers against B.1.1.7 (alpha) and B.1.617.2 (delta) variants on the 28th day after the boost dose. Results were compared with our previous study cohorts who received the same prime-boost vaccinations at 4- and 8-week intervals. Compared to other heterologous vaccination groups, the 12-week interval group had higher neutralizing antibody titers against SARS-CoV-2 variants than the 4-week interval group and was similar to the 8-week interval group at day 28. Adverse reactions after the boost dose were mild and transient. Our results support deploying viral vectored and mRNA vaccines in a flexible schedule with intervals from 8 to 12 weeks.

Fatal Cerebral Venous Thrombosis in a Pregnant Woman with Inherited Antithrombin Deficiency after BNT162b2 mRNA COVID-19 Vaccination.

Antithrombin deficiency is a high-risk factor for venous thromboembolism during pregnancy, whereas cerebral venous thrombosis is rare. Cerebral venous thrombosis related to coronavirus disease 2019 (COVID-19) vaccines has been reported; however, there are a few reports of cerebral venous thrombosis after a messenger RNA (mRNA) vaccination. A 25-year-old female in her sixth week of pregnancy presented with headache 24 days after BNT162b2 mRNA COVID-19 vaccination. The following day, she presented with altered sensorium and was diagnosed with severe cerebral venous thrombosis. She demonstrated heparin resistance and was found to have an inherited antithrombin deficiency. A heterozygous missense variant in SERPINC1 (c.379T>C, p.Cys127Arg, 'AT Morioka') was detected by DNA analysis. Despite intensive care with unfractionated heparin, antithrombin concentrate, and repeated endovascular treatments, she died on the sixth day of hospitalization. Cerebral venous thrombosis in pregnant women with an antithrombin deficiency can follow a rapid and fatal course. Treatment with unfractionated heparin and antithrombin concentrate may be ineffective in severe cerebral venous thrombosis cases with antithrombin deficiency. Early recognition of antithrombin deficiency and an immediate switch to other anticoagulants may be required. Although the association between cerebral venous thrombosis and the vaccine is uncertain, COVID-19 vaccinations may require careful evaluation for patients with prothrombic factors.

Effectiveness of messenger RNA vaccines against infection with SARS-CoV-2 during the periods of Delta and Omicron variant predominance in Japan: the Vaccine Effectiveness, Networking, and Universal Safety (VENUS) study.

OBJECTIVES: We aimed to evaluate COVID-19 messenger RNA vaccine effectiveness during the Delta- and Omicron-predominant periods in Japan. METHODS: We conducted a population-based cohort study among individuals aged 16-64 years during two periods: the Delta-predominant period (July 1-December 31, 2021) and the Omicron-predominant period (January 1-March 29, 2022). RESULTS: When comparing individuals who were vaccinated with those who were unvaccinated, the effectiveness of a second dose against symptomatic infection was 89.8% (95% confidence interval [CI]: 80.5-94.7%) during the Delta-predominant period and 21.2% (95% CI: 11.0-30.3%) during the Omicron-predominant period. The effectiveness of a third dose against symptomatic infection was 71.8% (95% CI: 60.1-80.1%) during the Omicron-predominant period. CONCLUSION: Vaccine effectiveness against symptomatic infection decreased during the Omicron-predominant period but was maintained by a third dose.

A case report of unilateral cervical lymphadenopathy and multiple cranial neuropathies following mRNA-COVID-19 vaccination.

BACKGROUND: We report a rare case of ipsilateral multiple cranial neuropathy and ipsilateral lymphadenopathy following mRNA-COVID-19 vaccination. CASE PRESENTATION: A 41-year-old male visited our emergency room complaining of dysphagia and hoarseness that started a week after receiving COVID19 mRNA vaccination (in his right arm). During his hospitalization, he also complained of right side hearing loss and diplopia. Neurological examination depicted a right IV nerve palsy, ipsilateral facial paresthesia and peripheral facial paresis. Otorinolaryngological examination revealed right vocal cord paralysis. A brain magnetic resonance imaging showed enhancement of the right VII and VIII cranial nerves in the auditory canal. The lumbar puncture revealed increased protein concentration and lymphocytic pleocytosis in the cerebrospinal fluid (CSF). Additionally, a neck computed tomography (CT) scan showed a swollen right supraclavicular lymph node. We hypothesize that the ipsilateral cranial neuropathies of IV, VI, VII, VIII and X, associated with cervical lymphadenopathy, was possible caused by a post-vaccination immune-mediated reaction. The patient was treated with a 5-day course of intravenous methylprednisolone (1000 mg/day), and a gradual improvement was observed. CONCLUSIONS: Similarly, to other vaccines, it is possibly that also mRNA vaccines may act as triggers of non-specific autoimmune neurological syndromes.

Individual-level social capital and COVID-19 vaccine hesitancy in Japan: a cross-sectional study.

To reduce vaccine hesitancy, it is important to identify factors that can intervene at the individual or community level. Social capital is a possible factor because it is associated with various vaccine hesitancy, such as for measles and influenza. However, limited studies have explored the association between social capital and vaccination for COVID-19, which is an unprecedented pandemic and infodemic. Therefore, this study aimed to clarify the association between social capital and COVID-19 vaccination during the pandemic. This cross-sectional study used quota sampling for an online-based survey. Participants were asked whether they had previously been vaccinated for COVID-19 and their intention to receive a COVID-19 vaccine booster. Social capital was evaluated using three measures (individual-level civic participation, social cohesion, and reciprocity). Multiple logistic regression analysis was performed to clarify the association between social capital and previous COVID-19 vaccination status as well as intention to receive a COVID-19 booster. Participants were 2,313 individuals, of whom 87.2% had received a COVID-19 vaccine; 72.3% intended to obtain a COVID-19 booster. Individuals with any social capital are more likely to receive a COVID-19 vaccination than those with none (OR: 1.73, 95%CI: 1.18-2.54; OR: 1.58, 95%CI: 1.22-2.05; OR: 3.05, 95%CI: 2.15-4.33). These indicators were also associated with the intention to receive a COVID-19 booster. Thus, our results suggest that among the general public, those with individual-level social capital are more likely to receive a COVID-19 vaccination than those with none. Social capital may be a factor that can reduce vaccine hesitancy during a pandemic.

Immune response and safety of heterologous ChAdOx1-nCoV-19/mRNA-1273 vaccination compared with homologous ChAdOx1-nCoV-19 or homologous mRNA-1273 vaccination.

BACKGROUND/PURPOSE: Efficacy and safety data of heterologous prime-boost vaccination against SARS-CoV-2 remains limited. METHODS: We recruited adult volunteers for homologous or heterologous prime-boost vaccinations with adenoviral (ChAdOx1, AstraZeneca) and/or mRNA (mRNA-1273, Moderna) vaccines. Four groups of prime-boost vaccination schedules were designed: Group 1, ChAdOx1/ChAdOx1 8 weeks apart; Group 2, ChAdOx1/mRNA-1273 8 weeks apart; Group 3, ChAdOx1/mRNA-1273 4 weeks apart; and Group 4, mRNA-1273/mRNA-1273 4 weeks apart. The primary outcome was serum anti-SARS-CoV-2 IgG titers and neutralizing antibody titers against B.1.1.7 (alpha) and B.1.617.2 (delta) variants on day 28 after the second dose. Adverse events were recorded up until 84 days after the second dose. RESULTS: We enrolled 399 participants with a median age of 41 years and 75% were female. On day 28 after the second dose, the anti-SARS-CoV-2 IgG titers of both heterologous vaccinations (Group 2 and Group 3) were significantly higher than that of homologous ChAdOx1 vaccination (Group 1), and comparable with homologous mRNA-1273 vaccination (Group 4). The heterologous vaccination group had better neutralizing antibody responses against the alpha and delta variant as compared to the homologous ChAdOx1 group. Most of the adverse events (AEs) were mild and transient. AEs were less frequent when heterologous boosting was done at 8 weeks rather than at 4 weeks. CONCLUSION: Heterologous ChAdOx1/mRNA-1273 vaccination provided higher immunogenicity than homologous ChAdOx1 vaccination and comparable immunogenicity with the homologous mRNA-1273 vaccination. Our results support the safety and efficacy of heterologous prime-boost vaccination using the ChAdOx1 and mRNA-1273 COVID-19 vaccines. (ClinicalTrials.gov number, NCT05074368).

Factors associated with anti-SARS-CoV-2 spike antibody titers after a second BNT162b2 mRNA COVID-19 vaccination in Japanese hemodialysis patients.

BACKGROUND: We investigated factors associated with the anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibody titer after the second dose of the BNT162b2 messenger RNA coronavirus disease 2019 (COVID-19) vaccine in Japanese patients undergoing hemodialysis. METHODS: Overall, 75 patients (41 men, 34 women; mean age 71.4 ± 12.2 years) with a hemodialysis duration of 5.7 ± 6.1 [interquartile range, 1.0-8.5] years were enrolled in this single-center, prospective, cross-sectional study. We used multiple linear regression analysis to determine the relationships of the anti-SARS-CoV-2 spike antibody titer with patient demographic and clinical parameters. We also compared the anti-SARS-CoV-2 spike antibody titer between hemodialysis patients and 22 healthcare workers (10 men, 12 women; mean age 48.5 ± 14.4 years). RESULTS: Autoimmune disease presence (standard coefficient [ß] = - 0.290, p = 0.018), lymphocyte counts (ß = 0.261, p = 0.015), hemoglobin levels (ß = 0.290, p = 0.009), and blood urea nitrogen concentrations (ß = 0.254, p = 0.033) were significantly and independently correlated with the log-anti-SARS-CoV-2 spike antibody titer. The anti-SARS-CoV-2 spike antibody titer was significantly lower in hemodialysis patients than in healthcare workers (3589 ± 3921 [813-4468] vs. 12,634 ± 18,804 [3472-10,257] AU/mL; p < 0.002). CONCLUSIONS: Autoimmune disease presence, lymphocyte counts, hemoglobin levels, and blood urea nitrogen concentrations were associated with the anti-SARS-CoV-2 spike antibody titer after the second dose of the BNT162b2 messenger RNA COVID-19 vaccine in Japanese patients undergoing hemodialysis.

COVID-19 vaccination among pregnant people in the United States: a systematic review.

OBJECTIVE: Pregnant people are at increased risk of COVID-19-related morbidity and mortality, and vaccination presents an important strategy for preventing negative outcomes. However, pregnant people were not included in vaccine trials, and there are limited data on COVID-19 vaccines during pregnancy. The objectives of this systematic review were to identify the safety, immunogenicity, effectiveness, and acceptance of COVID-19 vaccination among pregnant people in the United States. DATA SOURCES: Four databases (PubMed, Web of Science, CINAHL, and Google Scholar) were used to identify eligible studies published from January 1, 2020 through February 6, 2022. STUDY ELIGIBILITY CRITERIA: Inclusion criteria were peer-reviewed empirical research conducted in the United States, publications in English, and research addressing 1 of the following topics: safety, immunogenicity, effectiveness, and acceptance of COVID-19 vaccination among pregnant people. METHODS: A narrative synthesis approach was used to synthesize findings. Critical appraisal was done using the JBI (formerly Joanna Briggs Institute) tool. RESULTS: Thirty-two studies were identified. Most studies (n=24) reported the use of Pfizer and Moderna COVID-19 vaccines among pregnant people; only 6 reported the Janssen vaccine. Of the 32 studies, 11 examined COVID-19 vaccine safety, 10 investigated immunogenicity and effectiveness, and 11 assessed vaccine acceptance among pregnant people. Injection-site pain and fatigue were the most common adverse events. One case study reported immune thrombocytopenia. COVID-19 vaccination did not increase the risk of adverse pregnancy or neonatal outcomes compared with unvaccinated pregnant people. After COVID-19 vaccination, pregnant people had a robust immune response, and vaccinations conferred protective immunity to newborns through breast milk and placental transfer. COVID-19 vaccine acceptance was low among pregnant people in the United States. African American race, Hispanic ethnicity, younger age, low education, previous refusal of the influenza vaccine, and lack of provider counseling were associated with low vaccine acceptance. CONCLUSION: Peer-reviewed studies support COVID-19 vaccine safety and protective effects on pregnant people and their newborns. Future studies that use rigorous methodologies and include diverse populations are needed to confirm current findings. In addition, targeted and tailored strategies are needed to improve vaccine acceptance, especially among minorities.

Serological Response to SARS-CoV-2 Messenger RNA Vaccine: Real-World Evidence from Italian Adult Population.

BACKGROUND: This study aims to investigate the extent of the BNT162b2 mRNA vaccine-induced antibodies against SARS-CoV-2 in a large cohort of Italian subjects belonging to the early vaccinated cohort in Italy. METHODS: A prospective study was conducted between December 2020 and May 2021. Three blood samples were collected for each participant: one at the time of the first vaccine dose (T0), one at the time of the second vaccine dose, (T1) and the third 30 days after this last dose (T2). RESULTS: We enrolled 2591 fully vaccinated subjects; 16.5% were frail subjects, and 9.8% were over 80 years old. Overall, 98.1% of subjects were seropositive when tested at T2, and 76.3% developed an anti-S IgG titer ≥4160 AU/mL, which is adequate to develop viral neutralizing antibodies. Seronegative subjects at T1 were more likely to remain seronegative at T2 or to develop a low-intermediate anti-S IgG titer (51-4159 AU/mL). CONCLUSIONS: In summary, vaccination leads to detectable anti-S IgG titer in nearly all vaccine recipients. Stratification of the seroconversion level could be useful to promptly identify high-risk groups who may not develop a viral neutralizing response, even in the presence of seroconversion, and therefore may remain at higher risk of infection, despite vaccination.