Vaccine Production

Introduction Vaccines are biological products that elicit a protective immune response. The details of the manufacturing processes are varied depending on the particular characteristics of the vaccine. There are classically, three basic types of vaccines against viral and bacterial pathogens (For mRNA-, DNA- and vector-vaccines see Chapters 7, 8, 9): Live-attenuated. Killed (non-live). Subunit. “Classical” Vaccine Production The basic classical process includes 5 phases: expression, harvest, inactivation, purification, formulation. The expression systems for viral and bacterial vaccines are distinct. Bacterial expression is performed in fermenters. Viral vaccines are produced in animal cell culture or embryonated chicken eggs. Processes for whole viral or bacterial vaccines often involve only limited processing after expression. Subunit vaccines routinely require the most purification to separate the product from other contaminants. Challenges Challenges for bacterial vaccines include testing to ensure the safety and efficacy of the product. Inactivation procedures need to be carefully controlled. Live attenuated vaccines need to be tested to ensure the vaccine strains are still safe and effective. Viral vaccines require testing to ensure foreign infectious agents are not introduced during processing. Both cultured cells and egg present risks for infection. Live viral vaccines and gene vectors need to be carefully engineered and tested to minimize safety concerns. Highly variable vaccine targets such as influenza need to be re-adapted to current circulating strains.

Reporting of Acute Inflammatory Neuropathies with COVID-19 Vaccines: Subgroup Disproportionality Analyses in VigiBase

Since marketing authorization, cases of neuralgic amyotrophy (NA), facial paralysis/Bell’s palsy (FP/BP), and Guillain-Barré syndrome (GBS) were reported with COVID-19 vaccines of different technologies. This study aimed to assess whether NA, FP/BP, and GBS were more frequently reported in VigiBase with COVID-19 vaccines (of any technologies) than with other viral vaccines, over the full database and across potential risk groups by sex and age. The reporting odds ratio (ROR) with 95% confidence interval (95% CI) was used as the measure of disproportionality and subgroup disproportionality analyses were performed by sex and age. Out of 808,906 safety reports with COVID-19 vaccines, 57 (0.01%) reported NA, 3320 (0.4%) FP/BP, and 632 (0.1%) GBS. There were not signals of disproportionate reporting for NA and GBS with COVID-19 vaccines against other viral vaccines. FP/BP was disproportionately more frequently reported with COVID-19 vaccines than with other viral vaccines over the full database (ROR 1.12, 95%CI 1.07–1.17), in males (ROR 1.65, 95%CI 1.54–1.78) and in age subgroups 65–74 years (ROR 1.21, 95%CI 1.05–1.39) and ≥75 years (ROR 1.84, 95%CI 1.52–2.22). Albeit not proving causation, these findings might support clinicians in decision-making for patients potentially at risk for developing an acute inflammatory neuropathy with COVID-19 vaccines.

Looking in the medicine cabinet: methods for using real-world data to assess the impact of measles, mumps and rubella (MMR) and recombinant adjuvanted varicella-zoster vaccines on coronavirus disease 2019 (COVID-19) prevention and case fatality

Background: Analysis of real-world data can be used to identify promising leads and dead ends among products being repurposed for clinical practice for coronavirus disease 2019 (COVID-19). This paper uses real-world data from Cerner Labs collected from 90 source institutions in the United States to assess the potential impact of live viral vaccines on COVID-19 case fatality rates. Methods: We identified 373,032 polymerase chase reaction (PCR)-positive COVID-19 cases in the Cerner Labs database between 01-MAR-2020 and 31-DEC-2020 and identified patients that had received measles, mumps and rubella (MMR) or a recombinant adjuvanted varicella-zoster vaccine within the previous 5 years. We calculated heterogeneity scores to support interpretation of results across institutions, and used stepwise forward variable selection to construct covariable-based propensity scores. These scores were used to match cases and control for biasing and confounding issues inherent in observational data. Results: Neither the recombinant adjuvanted varicella-zoster vaccine nor MMR showed significant efficacy in prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We could not derive clinically significant results on the impact of MMR for case fatality rates due to persistently high rates of heterogeneity between institutions. However, we were able to achieve acceptable levels of heterogeneity for the analysis of the recombinant adjuvanted varicella-zoster vaccine, and found a clinically meaningful benefit of reduced case fatality rate, with an odds ratio of 0.43 (95% confidence interval [CI]: 0.38 – 0.48). Conclusions: Using propensity score matching and heterogeneity statistics can help guide our interpretation of real-world data, and rigorous statistical methods are needed to reduce bias or disparities in data interpretation. Applying these methods to the impact of live viral vaccines on COVID-19 case fatalities yields actionable findings for further analysis.

A Relapsing Immune Thrombocytopenia Case in a Patient Following COVID-19 Vaccination

There are several vaccines developed against COVID-19 infection. Inactivated viral vaccines are usually well tolerated. We aimed to present a relapsing immune thrombocytopenia case following inactive COVID-19 vaccine. Here we report a case of relapsing immune thrombocytopenia following inactivated viral vaccine against COVID-19 in a 60-year-old woman with a history of immune thrombocytopenia. The patient responded well to dexamethasone treatment and was discharged from the hospital with full recovery. We suggest that physicians seek the history of a recent inactivate COVID-19 vaccine shot in patients with immune thrombocytopenia.

Live Viral Vaccine Neurovirulence Screening: Current and Future Models

Live viral vaccines are one of the most successful methods for controlling viral infections but require strong evidence to indicate that they are properly attenuated. Screening for residual neurovirulence is an important aspect for live viral vaccines against potentially neurovirulent diseases. Approximately half of all emerging viral diseases have neurological effects, so testing of future vaccines will need to be rapid and accurate. The current method, the monkey neurovirulence test (MNVT), shows limited translatability for human diseases and does not account for different viral pathogenic mechanisms. This review discusses the MNVT and potential alternative models, including in vivo and in vitro methods. The advantages and disadvantages of these methods are discussed, and there are promising data indicating high levels of translatability. There is a need to investigate these models more thoroughly and to devise more accurate and rapid alternatives to the MNVT.