Additional Vaccine Research Articles

CTIM-12. IMMUNOGENICITY OF AN ADDITIONAL DOSE OF COVID-19 VACCINE IN FULLY VACCINATED PATIENTS WITH GLIOMA TO EVALUATE NEW NATIONAL VACCINATION GUIDELINES - A PROSPECTIVE COHORT STUDY

Abstract Patients diagnosed with glioma belong to a high-risk group during the COVID-19 pandemic. These patients have a compromised immune function due to the malignancy itself, specific anticancer therapies such as temozolomide and symptom-alleviating corticosteroid treatments. While earlier studies have reported successful seroconversion after SARS-CoV-2 immunization in oncological patients, inclusive of those with glioma, the resulting antibody titers remain markedly inferior compared to the healthy population. The recent modification of COVID-19 vaccine guidelines in Germany advocates an additional annual vaccination for glioma patients. Our prospective cohort study endeavors to delineate the immunogenicity in fully immunized glioma patients through assessment of humoral and adaptive immune response post-administration of the supplementary vaccine dose. In this single-center study, glioma patients undergoing tumor-specific therapy will receive an adjunctive dose of the COVID-19 vaccine in conjunction with the seasonal influenza vaccine. A cohort of 70 glioma patients is planned for inclusion, and a comparative analysis will be conducted against a control group consisting of healthy relatives and healthcare professionals. Blood samples will be procured at two distinct intervals: T1, preceding the extra vaccine administration, and T2, 28 days following vaccination. Immunogenicity will be assessed by quantifying anti-SARS-CoV-2 spike (S) protein and nucleocapsid protein (N) concentrations and T-cell responses ascertained using the ELISPOT assay and flow cytometry. In parallel, a comprehensive evaluation of clinical data relevant to therapeutic interventions and corticosteroid usage will be undertaken. At the time of abstract submission, patient recruitment is in progress. Preliminary immunological and clinical data from this investigation, which seek to appraise immune competence and ascertain the clinical implications of the revised COVID-19 vaccination guidelines in glioma patients, will be presented.

Longitudinal increase of humoral responses after four SARS-CoV-2 vaccinations and infection in MS patients on fingolimod

Background: Humoral responses after SARS-CoV-2 vaccination are greatly impaired in multiple sclerosis (MS) patients on fingolimod. Effects of repeated vaccination and infections on long-term responses are unclear. Methods: Prospective study in 60 MS patients on fingolimod measuring humoral responses after up to four vaccinations and 8 months after fourth vaccination. Results: Anti-WH1 antibody titers increased with each additional vaccination. At long-term follow-up titers increased further and most patients developed new humoral responses against the BA.1 omicron variant. Conclusion: Repeated SARS-CoV-2 vaccinations boost humoral immunity and, probably together with SARS-CoV-2 infections, induce humoral responses on the long-term in almost all patients.

The potential clinical impact and cost-effectiveness of the updated COVID-19 mRNA fall 2023 vaccines in the United States

Aims To assess the potential clinical impact and cost-effectiveness of COVID-19 mRNA vaccines updated for fall 2023 in adults aged ≥18 years over a 1-year analytic time horizon (September 2023-August 2024). Materials and methods A compartmental Susceptible-Exposed-Infected-Recovered model was updated to reflect COVID-19 cases in summer 2023. The numbers of symptomatic infections, COVID-19–related hospitalizations and deaths, and costs and quality-adjusted life-years (QALYs) gained were calculated using a decision tree model. The incremental cost-effectiveness ratio (ICER) of a Moderna updated mRNA fall 2023 vaccine (Moderna Fall Campaign) was compared to no additional vaccination. Potential differences between the Moderna and the Pfizer-BioNTech fall 2023 vaccines were also examined. Results Base case results suggest that the Moderna Fall Campaign would decrease the expected 64.2 million symptomatic infections by 7.2 million (11%) to 57.0 million. COVID-19–related hospitalizations and deaths are expected to decline by 343,000 (-29%) and 50,500 (-33%), respectively. The Moderna Fall Campaign would increase QALYs by 740,880 and healthcare costs by $5.7 billion relative to no vaccine, yielding an ICER of $7700 per QALY gained. Using a societal cost perspective, the ICER is $2100. Sensitivity analyses suggest that vaccine effectiveness, COVID-19 incidence, hospitalization rates, and costs drive cost-effectiveness. With a relative vaccine effectiveness of 5.1% for infection and 9.8% for hospitalization for the Moderna vaccine versus the Pfizer-BioNTech vaccine, use of the Moderna vaccine is expected to prevent 24,000 more hospitalizations and 3300 more deaths than the Pfizer-BioNTech vaccine. Limitations and conclusions As COVID-19 becomes endemic, future incidence, including patterns of infection, are highly uncertain. The effectiveness of fall 2023 vaccines is unknown, and it is unclear when a new variant that evades natural or vaccine immunity will emerge. Despite these limitations, our model predicts the Moderna Fall Campaign vaccine is highly cost-effective across all sensitivity analyses.

One-year antibody durability induced by EuCorVac-19, a liposome-displayed COVID-19 receptor binding domain subunit vaccine, in healthy Korean subjects

ObjectiveEuCorVac-19 (ECV-19), an adjuvanted liposome-displayed receptor binding domain (RBD) COVID-19 vaccine, previously reported interim Phase 2 trial results showing induction of neutralizing antibodies 3 weeks after prime-boost immunization. The objective of this study was to determine the longer-term antibody response of the vaccine. MethodsTo assess immunogenicity 6 and 12 months after vaccination, participants in the Phase 2 trial (NCT04783311) were excluded if they: 1) withdrew, 2) reported COVID-19 infection or additional vaccination, or 3) exhibited increasing Spike (S) antibodies (representing possible non-reported infection). Following exclusions, of the 197 initial subjects, anti-S IgG antibodies and neutralizing antibodies were further assessed in 124 subjects at the 6-month timepoint, and 36 subjects at the 12-month timepoint. ResultsMedian anti-S antibody half-life was 52 days (interquartile range [IQR]:42-70), in the “early” period from 3 weeks to 6 months, and 130 days (IQR:97-169) in the “late” period from 6 to 12 months. There was a negative correlation between initial antibody titer and half-life. Anti-S and neutralizing antibody responses were correlated. Neutralizing antibody responses showed longer half-lives; the early period had a median half-life of 120 days (IQR:81-207), and the late period had a median half-life of 214 days (IQR:140-550). ConclusionThese data establish antibody durability of ECV-19, using a framework to analyze COVID-19 vaccine-induced antibodies during periods of high infection.

The fourth COVID-19 vaccine dose increased the neutralizing antibody response against the SARS-CoV-2 Omicron (B.1.1.529) variant in a diverse Brazilian population.

Most of the original immunization regimens against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were composed of two doses, followed by a subsequent third booster dose to control the Omicron variant and hence coronavirus disease 2019 (COVID-19). However, most data generated regarding the fourth dose were not based on the general population. Therefore, this study aimed to verify the effect of the fourth COVID-19 vaccine dose in a diverse Brazilian population. This retrospective observational study was conducted between May and September 2022. We gathered data on the vaccine regimens and COVID-19 serologic status from 266 healthy volunteers who received three or four vaccine doses, as well as COVID-19 diagnosis and viral genome sequencing from 457 patients with flu-like symptoms. In addition, we conducted immunoinformatic analysis to assess the conserved epitopes in the locally circulating viruses. We showed that the fourth dose did not increase the serum levels of antiviral antibodies, as measured by enzyme-linked immunosorbent assay. However, it significantly increased neutralizing antibody (NAb) titers against the Omicron variant. All viral sequences generated in this study were Omicron subvariants, mainly B.A.5.1. Notably, most NAb epitopes present in the wild-type SARS-CoV-2 were not detected among the circulating Omicron subvariants. None of the volunteers who received the third or fourth doses presented COVID-19 for at least 1 year before the study period. Altogether, these results indicate that the fourth vaccine dose increases the serum levels of NAbs that recognize highly conserved epitopes in Omicron subvariants.IMPORTANCESeveral additional COVID-19 vaccine doses were administered in the Brazilian population to prevent the disease caused by the B.1.1.529 (Omicron) variant. The efficacy of a third dose as a booster is already well described. However, it is important to clarify the humoral immune response gain induced by a fourth dose. In this study, we evaluate the effect of the fourth COVID-19 vaccine dose in a diverse Brazilian population, considering a real-life context. Our study reveals that the fourth dose of the COVID-19 vaccine increased the neutralizing antibody response against SARS-CoV-2 Omicron and significantly contributed in the reduction of the disease caused by this variant.

Improving bivalent COVID-19 vaccination rates among adult patients with cancer: An ASCO/CDC initiative.

427 Background: Vaccines protect immunosuppressed cancer patients from developing severe illness, hospitalization, and death. However, vaccination rates in cancer patients remain low, jeopardizing their long-term outcomes. Kaiser Permanente Northern California (KPNC) is one of eight health systems in the U.S. selected to participate in the Specialty Societies Advancing Adult Immunization Project awarded to ASCO and funded by the CDC and the Council of Medical Specialty Societies (CMSS). In conjunction with the ASCO Quality Training Program, we assessed the barriers to bivalent COVID-19 vaccination and applied quality improvement initiatives to increase the vaccination rate for adult cancer patients at KP Roseville. Our aim was to achieve a 50% bivalent COVID-19 vaccination rate by June 2023. Methods: Our population of interest included adult cancer patients receiving intravenous or oral chemotherapy. To assess the barriers to bivalent COVID-19 vaccinations, we distributed 100 surveys to oncology patients. We then performed two PDSA (Plan-Do-Study-Act) cycles for quality improvement and monitored the trends in bivalent COVID-19 vaccination rates from 3/20/2023 to 5/25/2023 with data extracted from electronic health records. Results: Surveys were returned from 63 of 100 oncology patients (35 unvaccinated, 28 vaccinated). Barriers to bivalent COVID-19 vaccination included lack of awareness (37%), fear of interaction with treatment (17%), inconvenience (14%), did not want it (14%), did not elaborate (14%), and prior reaction to the vaccine (3%). We conducted PDSA cycle 1 from 3/20/2023 to 4/14/2023. To improve awareness, we added bivalent COVID-19 vaccine content to the mandatory class for new cancer patients and distributed educational flyers at the oncology clinic. Only 1 out of 61 attendees during this period received vaccination following the class. PDSA cycle 2 was conducted from 5/1/2023 to 5/25/2023. We updated the educational flyer with the latest FDA/CDC recommendations. We also implemented a bi-weekly onsite vaccine station at the oncology clinic waiting area to improve convenience. By 5/25/2023, 78 of 320 eligible oncology patients received bivalent COVID-19 vaccines. As a result, bivalent COVID-19 vaccination rates at KP Roseville increased from 45% to 49% by June 2023. Conclusions: Despite the survey showing a lack of awareness as a major barrier to vaccination, increased awareness by itself had minimal impact on bivalent COVID-19 vaccination rates. However, the addition of a convenient onsite vaccine station in the oncology clinic along with providing education resulted in an increase in vaccinations. Our interventions led to promising results (49%) in the setting of generalized vaccine fatigue in the U.S. Our future goal is to expand these efforts to other KPNC oncology centers, establish stable onsite vaccine stations and include additional vaccine types.

General principles of vaccination of patients with neuromuscular diseases

Vaccination is recognized as the most effective, safe, and cost-effective way to prevent infectious diseases and their complications. For patients with chronic diseases, and for patients with neuromuscular diseases in particular, vaccination is the highest priority for the prevention of infectious diseases. In the current literature, there is a lack of information describing the principles of vaccination of patients with spinal muscular atrophy and Duchenne muscular dystrophy. In patients with neuromuscular diseases, full immunization has to be done in accordance with the National calendar and recommendations with the introduction of an additional vaccine against such diseases as: rotavirus infection, pneumococcal infection (using an additional dose of 23-valent vaccine), meningococcal infection, virus human papilloma, respiratory viral infection. syncytial virus and influenza. In this regard, of particular importance is the development of recommendations describing the schemes for the use of vaccines in children suffering from spinal muscular atrophy and Duchenne muscular dystrophy.

Immune responses to SARS-CoV-2 mRNA vaccination in people with idiopathic CD4 lymphopenia

BackgroundThe immunogenicity of SARS-CoV-2 mRNA vaccines is variable in individuals with different inborn errors of immunity or acquired immune deficiencies and is yet unknown in people with idiopathic CD4 lymphopenia (ICL). ObjectiveDetermine the immunogenicity of mRNA vaccines in patients with ICL with a broad range of CD4 T-cell counts. MethodsSamples were collected from 25 patients with ICL and 23 age- and sex-matched healthy volunteers (HVs) after their second or third SARS-CoV-2 mRNA vaccine dose. Anti-spike and anti-receptor binding domain antibodies were measured. T-cell-receptor sequencing and stimulation assays were performed to quantify SARS-CoV-2-specific T-cell responses. ResultsThe median age of ICL participants was 51-years and their CD4 count was 150 cells/μl; eleven individuals had CD4 ≤100 cells/μL. Anti-spike IgG antibody levels were greater in HVs than in patients with ICL after 2-doses and 3-doses of mRNA vaccine. There was no detectable significant difference, however, in anti-spike IgG between HVs and those with ICL and CD4 >100 cells/μL. The depth of spike-specific T-cell responses, by T-cell receptor sequencing, was lower in individuals with ICL. Activation-induced markers and cytokine production of spike-specific CD4 T-cells in ICL did not differ significantly compared to HVs after two or three vaccine doses. ConclusionPatients with ICL and CD4 count >100 cells/μL can mount vigorous humoral and cellular immune responses to SARS-CoV-2 vaccination, however, those with more severe CD4 lymphopenia have blunted vaccine-induced immunity and may require additional vaccine doses and other risk mitigation strategies.

COVID-19 vaccine booster dose effectiveness among health workers: systematic review & meta-analysis

Abstract Background The COVID-19 pandemic still being a major public health issue. New vaccine products have been developed, approved, distributed and given primarily to Healthcare Workers (HCWs). The aim of this systematic review is to define the term of protection offered by the administration of EMA (European Medicines Agency)-approved COVID-19 vaccine booster dose for healthcare professionals, considering the Vaccine Effectiveness (VE) against SARS-CoV-2 infections. Methods A systematic research of the literature was carried out using PICO (Population, Intervention, Comparison, Outcomes) model and following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Then, a meta-analysis was carried out. Results Starting from 1241 obtained, 5 studies met the inclusion criteria. All studies dealt with only first booster dose. VE against infection was estimated, with Comirnaty booster dose, between 50% (95% C.I. 42-56%) and 86% (95% C.I. 79-90%) and, with Spikevax booster dose, between 56% (95% C.I. 45-65%) and 96% (95% C.I. 82-99%). The meta-analysis showed an overall VE of 73% (95% C.I. 70-76%). Conclusions High VE levels among HCWs in the prevention of SARS-CoV-2 infections, which rapidly decline, were reported. Hence, the periodic administration of additional booster vaccine doses would be indicated. Key messages • EMA-approved COVID-19 vaccine booster doses are effective among healthcare workers, one of the categories most at risk: they can protect them from infections, keeping them able to work. • Due to the effectiveness short duration, periodic administration of additional booster doses would be indicated among healthcare workers.

Characterization of the antispike IgG immune response to COVID-19 vaccines in people with a wide variety of immunodeficiencies.

Research on coronavirus disease 2019 vaccination in immune-deficient/disordered people (IDP) has focused on cancer and organ transplantation populations. In a prospective cohort of 195 IDP and 35 healthy volunteers (HV), antispike immunoglobulin G (IgG) was detected in 88% of IDP after dose 2, increasing to 93% by 6 months after dose 3. Despite high seroconversion, median IgG levels for IDP never surpassed one-third that of HV. IgG binding to Omicron BA.1 was lowest among variants. Angiotensin-converting enzyme 2 pseudo-neutralization only modestly correlated with antispike IgG concentration. IgG levels were not significantly altered by receipt of different messenger RNA-based vaccines, immunomodulating treatments, and prior severe acute respiratory syndrome coronavirus 2 infections. While our data show that three doses of coronavirus disease 2019 vaccinations induce antispike IgG in most IDP, additional doses are needed to increase protection. Because of the notably reduced IgG response to Omicron BA.1, the efficacy of additional vaccinations, including bivalent vaccines, should be studied in this population.

Hemalin vaccination modulates the host immune response and reproductive cycle of Haemaphysalis longicornis

Haemaphysalis longicornis can transmit high varieties of tick-borne pathogens (TBPs), and a primary strategy for preventing the transmission of those TBPs is to control ticks. Hemalin, a thrombin inhibitor of the Kunitz-type family and a crucial component in H. longicornis feeding process has been isolated from parthenogentic ticks. This study aimed to evaluate the validity of a recombinant Hemalin (rHlHemalin) vaccination as an anti-tick vaccine against H. longicornis in rabbits to find a new candidate for an effective tick control. In this study, mouse splenocytes were isolated and used to investigate immune responses after rHlHemalin stimulation. The rabbits were vaccinated with the rHlHemalin protein. After tick challenges, body weight at engorgement, egg mass, and the reproductive cycle of H. longicornis were evaluated. To confirm the vaccination, the passive immunization tests of α-rHlHemalin sera were performed. The results showed that the rHlHemalin protein could stimulate cytokine production in mouse splenocytes. Vaccination assay revealed that the periods from tick infestations to egg-hatch in the vaccination group were significantly longer than those in the phosphate buffer saline (PBS) group (P = 0.0003). In addition, the tick body weight at engorgement (P = 0.0019) and egg mass at 10 days after oviposition (P = 0.0232) were higher than those in the PBS group. These findings were consistent with the current passive immunization results and suggest rHlHemalin vaccination extended the reproductive cycle in H. longicornis but did not decrease the body weight at engorgement or weight of egg mass. Therefore, it is debatable whether Hemalin vaccination is highly-effective anti-tick vaccine or not. However, due to the importance of thrombin inhibitors in tick blood feeding and blood digestion, additional inhibitor-based vaccines should be developed aiming to find an effective and environmentally friendly biological strategy to combat ticks.

Mapping SARS-CoV-2 antigenic relationships and serological responses.

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, multiple variants escaping preexisting immunity emerged, causing reinfections of previously exposed individuals. Here, we used antigenic cartography to analyze patterns of cross-reactivity among 21 variants and 15 groups of human sera obtained after primary infection with 10 different variants or after messenger RNA (mRNA)-1273 or mRNA-1273.351 vaccination. We found antigenic differences among pre-Omicron variants caused by substitutions at spike-protein positions 417, 452, 484, and 501. Quantifying changes in response breadth over time and with additional vaccine doses, our results show the largest increase between 4 weeks and >3 months after a second dose. We found changes in immunodominance of different spike regions, depending on the variant an individual was first exposed to, with implications for variant risk assessment and vaccine-strain selection.

FRI461 Two-years Course Of Subacute Thyroiditis After COVID-19 Vaccination: A Case Report

Abstract Disclosure: S. Yoshida: None. COVID-19 has been reported to cause subacute thyroiditis. Furthermore, the literature includes cases of COVID-19 vaccine-related subacute thyroiditis, but few reports describe the long-term course of vaccine-induced subacute thyroiditis. Herein, we report the case of a 47-year-old woman with no medical history who developed subacute thyroiditis after mRNA COVID-19 vaccination and was followed up for 2 years. Her fever persisted after the second dose of the COVID-19 vaccine, and she became aware of left anterior neck pain 8 days later. There were no infectious disease symptoms or signs in the patient’s history or at a recent physical examination. All thyroid autoantibodies were negative. On ultrasound, the thyroid gland was diffusely enlarged, and internal echogenicity was diffusely hypoechoic, coarse, and color Doppler blood flow signals were decreased without confinement to the pain area. She was diagnosed with subacute thyroiditis with tender thyroid swelling, thyrotoxicosis, and an inflammatory reaction. It was suspected that there was a causal link between the onset of subacute thyroiditis and COVID-19 mRNA vaccination because it developed immediately after vaccination and there were no other obvious causes. She was started on prednisolone, and her symptoms improved rapidly, leading to hypothyroidism 1 month later. The swelling of the thyroid gland improved rapidly, and it became atrophic several months after the onset of subacute thyroiditis. She never received any additional vaccinations. Two years after the onset, there was no recurrence of subacute thyroiditis, thyroid atrophy persisted, and the patient required levothyroxine supplementation (100 µg/day). Subacute thyroiditis generally has a good prognosis and rarely leads to permanent hypothyroidism. Subacute thyroiditis due to vaccination may follow a different course than that due to typical viral infection, and we need to examine its long-term prognosis. Presentation: Friday, June 16, 2023

Analysis of Parents' Attitudes and Knowledge toward Immunization and How These Factors Influence Their Decisions to Vaccinate Their Children against Human Papilloma Virus (HPV).

Background and objectives: Vaccination hesitancy is a growing problem associated with decreasing chances for the elimination of vaccine-preventable diseases through immunization. This research was conducted to learn about parents' attitudes toward vaccination, particularly against HPV, in the context of their beliefs and fears regarding immunization and the impact of these views on their children's vaccination decisions. An additional goal was to determine what views or convictions most often lead to the phenomenon of delaying or refusing vaccinations, especially HPV vaccines, in the surveyed community. Materials and Methods: An online questionnaire was conducted in which parents marked how they vaccinated their children with mandatory vaccinations and whether they took the opportunity to protect their children with additional vaccinations, including HPV and COVID-19. Respondents also marked the extent to which they agreed with the statements, regarding the safety of vaccinations, doubts about them, as well as popular anti-vaccine myths. Results: A total of 250 questionnaires were collected with data on the immunization of 425 children. Associations between specific beliefs and vaccine abstention were established. The most motivating factor for vaccination against HPV was the parent's awareness that the virus HP is the cause of cancer. The most inhibiting factor was respondent's compliance with the opinion that HPV vaccines can affect the child's sexual activity. Conclusions: The results indicate that information campaigns are needed, especially focusing on vaccine safety and the regularity and transparency of monitoring adverse effects. The obtained results will be used to create educational interventions against vaccination hesitancy more adapted to local conditions.

Evaluation of the effectiveness of foot-and-mouth disease vaccination of animals in the buffer zone of the Republic of Armenia in 2016–2020

BackgroundFoot-and-mouth disease (FMD) is a high impact viral disease of livestock for which vaccines are extensively used for limiting the spread of infection. Armenia shares a border with both Turkey and Iran where FMD is endemic, making vaccination an important component of Armenia’s control strategy. Additionally, Armenian veterinary services utilize both passive and active monitoring for prevention control.MethodsWe sought to determine the immune status of animals vaccinated against FMD and to evaluate the effectiveness of our vaccination policy in Armenia. This was conducted in three regions including Shirak, Armavir, and Ararat Region which are located in the buffer zones that border Turkey and Iran. Through active monitoring in 2020, we studied blood serum samples from cattle and sheep using an enzyme immunoassay to determine the level of immune animals in these regions following the use of a polyvalent inactivated vaccine containing FMDV serotypes A, O, and Asia-1 that are relevant for this region. ELISA titers were assessed at 28, 90, and 180 days after vaccination in cattle of three age groups at the time of initial vaccination: 4–6 months, 6–18 months and ≥ 24 months of age with sheep of all ages.ResultsThe 3 age groups of cattle had similarly high levels of immunity with over 90% of the cattle showing a ≥ 50% protective titer 28 days after the first vaccination. By day 90, titers in cattle from the initial 4–18-month age groups dropped below 58% across the 3 serotypes and at or below 80% for the oldest cattle ≥ 24 months. Re-vaccination of cattle at 120 days did improve protective titers but never reached the level of immunity of the first vaccination. Sheep showed a similar rapid drop to less than 50% having a ≥ 50% protective titer at 90 days emphasizing the need for continual revaccination.ConclusionsThe results of this study have important implications for the current FMD vaccine policy in Armenia and improves our understanding of the rapid loss of protective titers over short periods. Since small ruminants are only vaccinated once per year and vaccination titers drop rapidly by 90 days suggests that they are vulnerable to FMD and that vaccination protocols need to be updated. Cattle should continue to be vaccinated every 3–6 months depending on their age to maintain a protective level of antibodies to protect them from FMD. More studies are needed to understand the possible role of small ruminants in the epidemiology of FMD and to evaluate revaccination at shorter intervals. These results show the concerns of rapid loss of protection to both cattle and small ruminants following 1 or more doses of commercial vaccines and that additional vaccines need to be evaluated in both groups to know how often they must be vaccinated to provide full protection. The addition of challenge studies should also be considered to better understand the level of protection as measured by serology and how it relates to protection from challenge. These results should be considered by anyone using these vaccines in cattle and sheep at longer than 3 month intervals.

The effect of COVID-19 vaccination status on all-cause mortality in patients hospitalised with COVID-19 in Hungary during the delta wave of the pandemic.

The high mortality of patients with coronavirus disease 2019 (COVID-19) is effectively reduced by vaccination. However, the effect of vaccination on mortality among hospitalised patients is under-researched. Thus, we investigated the effect of a full primary or an additional booster vaccination on in-hospital mortality among patients hospitalised with COVID-19 during the delta wave of the pandemic. This retrospective cohort included all patients (n = 430) admitted with COVID-19 at Semmelweis University Department of Medicine and Oncology in 01/OCT/2021-15/DEC/2021. Logistic regression models were built with COVID-19-associated in-hospital/30day-mortality as outcome with hierarchical entry of predictors of vaccination, vaccination status, measures of disease severity, and chronic comorbidities. Deceased COVID-19 patients were older and presented more frequently with cardiac complications, chronic kidney disease, and active malignancy, as well as higher levels of inflammatory markers, serum creatinine, and lower albumin compared to surviving patients (all p < 0.05). However, the rates of vaccination were similar (52-55%) in both groups. Based on the fully adjusted model, there was a linear decrease of mortality from no/incomplete vaccination (ref) through full primary (OR 0.69, 95% CI: 0.39-1.23) to booster vaccination (OR 0.31, 95% CI 0.13-0.72, p = 0.006). Although unadjusted mortality was similar among vaccinated and unvaccinated patients, this was explained by differences in comorbidities and disease severity. In adjusted models, a full primary and especially a booster vaccination improved survival of patients hospitalised with COVID-19 during the delta wave of the pandemic. Our findings may improve the quality of patient provider discussions at the time of admission.

Proteasome inhibition as a therapeutic target for the fungal pathogen Cryptococcus neoformans.

The current therapeutic challenges for treating fungal diseases demand new approaches and new drugs. A promising strategy involves combination therapy with agents of distinct mechanisms of action to increase fungicidal activity and limit the impact of mutations leading to resistance. In this study, we evaluated the antifungal potential of bortezomib by examining the inhibition of proteasome activity, cell proliferation, and capsule production by Cryptococcus neoformans, the causative agent of fungal meningoencephalitis. Chemical genetic screens with collections of deletion mutants identified potential druggable targets for combination therapy with bortezomib. In vitro assays of combinations of bortezomib with flucytosine, chlorpromazine, bafilomycin A1, copper sulfate, or hydroxyurea revealed antifungal effects against C. neoformans. Furthermore, combination treatment with bortezomib and flucytosine in a murine inhalation model of cryptococcosis resulted in the improvement of neurological functions and reduced fungal replication and dissemination, leading to a delay in disease progression. This study therefore highlights the utility of chemical genetic screens to identify new therapeutic approaches as well as the antifungal potential of proteasome inhibition. IMPORTANCE Fungal diseases of humans are difficult to treat, and there is a clear need for additional antifungal drugs, better diagnostics, effective vaccines, and new approaches to deal with emerging drug resistance. Fungi are challenging to control because they share many common biochemical functions with their mammalian hosts and it is therefore difficult to identify fungal-specific targets for drug development. One approach is to employ existing antifungal drugs in combination with agents that target common cellular processes at levels that are (ideally) not toxic for the host. We pursued this approach in this study by examining the potential of the clinically approved proteasome inhibitor bortezomib to influence the proliferation and virulence of Cryptococcus neoformans. We found that the combination of bortezomib with the anti-cryptococcal drug flucytosine improved the survival of infected mice, thus demonstrating the potential of this strategy for antifungal therapy.

Organization of Mass Vaccine Prevention in the Conditions of a Modern Megapolis

Relevance. Thanks to decisions taken at the national level, many countries have managed to significantly increase coverage with preventive vaccination and reduce mortality from vaccine-preventable diseases. However, the COVID-19 pandemic has recaptured the relevance of organizing mass vaccination. Based on the current epidemiological situation, characteristics of the population, peculiar features of infrastructure, available resources in individual country, and individual city, various organizational vaccination solutions have been developed and implemented. The Moscow-based experience of vaccinating against influenza at mobile vaccination sites near the Moscow metro stations in 2016 became the starting point in the development of new organizational forms and technologies for mass vaccination in a megapolis, that have been successfully adapted to the new conditions of the COVID19 pandemic.Aims. is to summarize foreign and Russian (exemplified by Moscow) experience in organizing mass vaccination.Material and methods. The study is based on the publication search results in Google and PubMed. The authors selected materials published in 2017– 2023. The implemented analysis of the long-term dynamics in the influenza incidence in the Russian Federation, the Central Federal District (CFD) and Moscow was based on data of the Federal State Statistical Observation Form No. 2 «Information on infectious and parasitic diseases» for 2013–2019.Results and discussion. The analysis of foreign experience shows that the development and implementation of new forms of mass vaccination cannot become a "standard project". In each region of the world, it is organized with due regard to the local economic, legal, social, medical, organizational and even cultural conditions. Vaccination of the population against influenza at mobile vaccination sites near the Moscow metro stations contributed to a 42.3% decrease in the incidence of influenza (from 24.6 in 2016 to 14.2 per 100,000 population in 2017). In 2019, the incidence of influenza in Moscow was 28.8% lower than the CFD one and 62.2% lower than the Russian rate. The recognized successful experience of deploying mobile vaccination sites near the metro stations has been significantly expanded to control the COVID-19 pandemic with mobile teams, vaccination sites in shopping centers, etc.Conclusion. The conducted research and literature data substantiate the deployment of additional vaccination sites to ensure the necessary coverage with vaccination within a short period of time.

SARS-CoV-2 spike-specific regulatory T cells (Treg) expand and develop memory in vaccine recipients suggesting a role for immune regulation in preventing severe symptoms in COVID-19

We enrolled healthy subjects that received 2 to 4 injections of mRNA-based vaccination to prevent COVID-19 months to a year from the last vaccine boost, and we found numerous SARS-CoV-2 spike-specific regulatory T cell (Treg) that developed T cell memory as effector memory T cells (TEM) and central memory T cells (TCM). CD4+ CD25high Treg expressed the chemokine receptor CCR6 in a considerable percentage, suggesting T cell homing to the vascular endothelium, lung and gut epithelial cells and brain. Treg phenotype was different than peripherally-induced Treg (pTreg) that revert from pro-inflammatory T cells under repeated stimulatory conditions, suggesting that SARS-CoV-2 spike-specific Treg differentiated from naïve T cells in tissues where the SARS-CoV-2 spike proteins were synthetized. Twenty two of 22 subjects studied responded to vaccination developing a spike-specific CD4+ T helper (Th)1 response, and 20 of 22 developing a spike-specific CD8+ cytotoxic T cells (CTL) response. However, in vaccine recipients the expansion of spike-specific pro-inflammatory T cells was less significant than the expansion of spike-specific Treg. Effector (TEM) and central memory (TCM) Treg were numerous as early as after two vaccine doses, with no significant differences following additional vaccine boosts. In co-culture experiments under stimulatory conditions, Treg regulated naïve T cell differentiation toward a pro-inflammatory phenotype and suppressed interferon (IFN)γ production by SARS-CoV-2-specific CD4 + Th1 cells.

Preclinical evaluation of a SARS-CoV-2 variant B.1.351-based candidate DNA vaccine

The SARS-CoV-2 pandemic revealed the critical shortfalls of global vaccine availability for emergent pathogens and the need for exploring additional vaccine platforms with rapid update potential in response to new variants. Thus, it remains essential, for the present evolving SARS-CoV-2/Covid-19 and future pandemics, to continuously develop and characterize new and different vaccine platforms. Here, we describe an expression-optimized DNA vaccine candidate based on the SARS-CoV-2 spike protein of the Beta variant (B.1.351), pNTC-Spike.351, and, in animal models, compare its immunogenicity with a similar DNA vaccine encoding the ancestral index strain spike protein, pNTC-Spike. Both DNA vaccines induced neutralizing antibodies and a Th1 biased immune response. In contrast to the index-specific vaccine, the Beta-specific DNA vaccine induced antibodies in mice and rabbits that, even at low levels, efficiently neutralize the otherwise antibody resistant Beta variant. It similarly neutralized unrelated variants bearing the neutralization resistant E484K spike mutation. Intensive priming using two vaccinations with pNTC-Spike and a single booster immunization with the pNTC-Spike.351 induced a more robust neutralizing antibody response with comparable magnitude against different variants of concern. Thus, DNA vaccine technology with heterologous spike protein prime-boost should be explored further using the Beta derived pNTC-Spike.351 to broaden neutralizing antibody responses against emerging variants of concern.