Self-amplifying RNA COVID-19 vaccine.

In November 2023, Japan's Ministry of Health, Labour and Welfare granted regulatory approval of ARCT-154, a self-amplifying RNA COVID-19 vaccine developed by Arcturus Therapeutics. Clinical trials showed comparable safety and efficacy using a lower dose compared to the mRNA vaccine BNT162b2. To view this Bench-to-Bedside, open or download the PDF.

Guillain-Barré syndrome and COVID-19 vaccination: a systematic review and meta-analysis.

BACKGROUND: Case-reports/series and cohorts of Guillain-Barré syndrome (GBS) associated with COVID-19 vaccination have been reported. METHODS: A systematic review and meta-analysis of cohort studies of GBS after COVID-19 vaccination was carried out. Incidence and incidence rate ratio for a number of vaccine doses and risk of GBS, also considering the specific vaccine technology, were calculated in a random-effects model. RESULTS: Of 554 citations retrieved, 518 were discarded as irrelevant. We finally included 15 studies. The random effect model yielded, regardless of the vaccine technology, 1.25 (95%CI 0.21; 2.83) GBS cases per million of COVID-19 vaccine doses, 3.93 (2.54; 5.54) cases per million doses for adenovirus-vectored vaccines and 0.69 (0.38; 1.06) cases per million doses for mRNA vaccines. The GBS risk was 2.6 times increased with the first dose. Regardless of the vaccine technology, the GBS risk was not increased but disaggregating the data it was 2.37 (1.67; 3.36) times increased for adenovirus-vectored vaccines and 0.32 (0.23; 0.47) for mRNA vaccines. Mortality for GBS after vaccination was 0.10 per million doses and 4.6 per GBS cases. CONCLUSIONS: Adenovirus-vectored vaccines showed a 2.4 times increased risk of GBS that was about seven times higher compared with mRNA-based vaccines. The decreased GBS risk associated with mRNA vaccines was possibly due to an elicited reduction of infections, including SARS-CoV-2, associated with GBS during the vaccination period. How adenovirus-vectored COVID-19 vaccines may trigger GBS is unclear and further studies should investigate the relationship between vaccine technologies and GBS risk.

Mucosal boosting enhances vaccine protection against SARS-CoV-2 in macaques.

A limitation of current SARS-CoV-2 vaccines is that they provide minimal protection against infection with current Omicron subvariants1,2, although they still provide protection against severe disease. Enhanced mucosal immunity may be required to block infection and onward transmission. Intranasal administration of current vaccines has proven inconsistent3-7, suggesting that alternative immunization strategies may be required. Here we show that intratracheal boosting with a bivalent Ad26-based SARS-CoV-2 vaccine results in substantial induction of mucosal humoral and cellular immunity and near-complete protection against SARS-CoV-2 BQ.1.1 challenge. A total of 40 previously immunized rhesus macaques were boosted with a bivalent Ad26 vaccine by the intramuscular, intranasal and intratracheal routes, or with a bivalent mRNA vaccine by the intranasal route. Ad26 boosting by the intratracheal route led to a substantial expansion of mucosal neutralizing antibodies, IgG and IgA binding antibodies, and CD8+ and CD4+ T cell responses, which exceeded those induced by Ad26 boosting by the intramuscular and intranasal routes. Intratracheal Ad26 boosting also led to robust upregulation of cytokine, natural killer, and T and B cell pathways in the lungs. After challenge with a high dose of SARS-CoV-2 BQ.1.1, intratracheal Ad26 boosting provided near-complete protection, whereas the other boosting strategies proved less effective. Protective efficacy correlated best with mucosal humoral and cellular immune responses. These data demonstrate that these immunization strategies induce robust mucosal immunity, suggesting the feasibility of developing vaccines that block respiratory viral infections.

Timely Second-Dose Completion of mRNA COVID-19 Vaccination at Community-Based and Mobile Vaccine Clinics in Maryland.

To assess factors associated with timely second-dose completion, we analyzed COVID-19 vaccine data from community-based and mobile vaccine clinics in Maryland. Overall, 85.3% of patients received a timely second dose. Factors associated with a timely second dose included Latino ethnicity (adjusted odds ratio [AOR] = 1.5; 95% confidence interval [CI] = 1.1, 2.0) and receipt of the first dose at community-based vaccine clinics (AOR = 2.1; 95% CI = 1.8, 2.5). Future health initiatives for underserved communities should focus on establishing vaccine clinics in trusted community spaces with culturally sensitive support. (Am J Public Health. 2023;113(9):947-951. https://doi.org/10.2105/AJPH.2023.307338).

Inmunización con vacunas ARN mensajero contra la COVID-19 en pacientes adolescentes con antecedente de síndrome inflamatorio multisistémico: serie de casos / Immunization with messenger RNA vaccines against COVID-19 in adolescents with a history of multisystem inflammatory

Los niños cursan mayormente la infección por el virus SARS-CoV-2 en forma leve. Sin embargo, de forma muy infrecuente algunos pueden desarrollar una patología con marcada gravedad denominada síndrome inflamatorio multisistémico en niños relacionado temporalmente con COVID-19 (SIM-C). Dado su reciente surgimiento, aún hay aspectos de su fisiopatología que se desconocen. La posibilidad de recidiva en caso de reinfección o ante la vacunación contra SARS-CoV-2 son nuevos interrogantes a los que nos enfrentamos. Reportamos una serie de casos de 4 pacientes adolescentes que cursaron SIM-C y meses después han sido vacunados contra SARS-CoV-2 con plataformas ARN mensajero (ARNm) sin presentar recurrencia de la enfermedad ni efectos adversos cardiológicos

In most cases, children with SARS-CoV-2 have a mild infection. However, very rarely, some children may develop a severe disease called multisystem inflammatory syndrome in children temporally associated with COVID-19 (MIS-C). Given its recent emergence, some aspects of its pathophysiology are still unknown. The possibility of recurrence in case of reinfection or SARS-CoV-2 vaccination are new questions we are facing. Here we report a case series of 4 adolescent patients who developed MIS-C and, months later, received the SARS-CoV-2 vaccine with messenger RNA (mRNA) platforms without disease recurrence or cardiac adverse events.

Risk of death following COVID-19 vaccination or positive SARS-CoV-2 test in young people in England.

Several studies have reported associations between COVID-19 vaccination and risk of cardiac diseases, especially in young people; the impact on mortality, however, remains unclear. We use national, linked electronic health data in England to assess the impact of COVID-19 vaccination and positive SARS-CoV-2 tests on the risk of cardiac and all-cause mortality in young people (12 to 29 years) using a self-controlled case series design. Here, we show there is no significant increase in cardiac or all-cause mortality in the 12 weeks following COVID-19 vaccination compared to more than 12 weeks after any dose. However, we find an increase in cardiac death in women after a first dose of non mRNA vaccines. A positive SARS-CoV-2 test is associated with increased cardiac and all-cause mortality among people vaccinated or unvaccinated at time of testing.

Physicians Say an Idaho House Bill That Would Criminalize Administering mRNA Vaccines Is an Attack on the Medical Profession-Even If It Doesn't Become Law.

This Medical News article discusses a bill introduced in Idaho that would ban administering mRNA vaccines.

Development of mRNA Vaccines/Therapeutics and Their Delivery System.

The rapid development of mRNA vaccines has contributed to the management of the current coronavirus disease 2019 (COVID-19) pandemic, suggesting that this technology may be used to manage future outbreaks of infectious diseases. Because the antigens targeted by mRNA vaccines can be easily altered by simply changing the sequence present in the coding region of mRNA structures, it is more appropriate to develop vaccines, especially during rapidly developing outbreaks of infectious diseases. In addition to allowing rapid development, mRNA vaccines have great potential in inducing successful antigen-specific immunity by expressing target antigens in cells and simultaneously triggering immune responses. Indeed, the two COVID-19 mRNA vaccines approved by the U.S. Food and Drug Administration have shown significant efficacy in preventing infections. The ability of mRNAs to produce target proteins that are defective in specific diseases has enabled the development of options to treat intractable diseases. Clinical applications of mRNA vaccines/therapeutics require strategies to safely deliver the RNA molecules into targeted cells. The present review summarizes current knowledge about mRNA vaccines/ therapeutics, their clinical applications, and their delivery strategies.

Immunization with messenger RNA vaccines against COVID-19 in adolescents with a history of multisystem inflammatory syndrome: a case series. / Inmunización con vacunas ARN mensajero contra la COVID-19 en pacientes adolescentes con antecedente de síndrome inflamatorio multisistémico: serie de casos.

In most cases, children with SARS-CoV-2 have a mild infection. However, very rarely, some children may develop a severe disease called multisystem inflammatory syndrome in children temporally associated with COVID-19 (MIS-C). Given its recent emergence, some aspects of its pathophysiology are still unknown. The possibility of recurrence in case of reinfection or SARS-CoV-2 vaccination are new questions we are facing. Here we report a case series of 4 adolescent patients who developed MIS-C and, months later, received the SARS-CoV-2 vaccine with messenger RNA (mRNA) platforms without disease recurrence or cardiac adverse events.

Los niños cursan mayormente la infección por el virus SARS-CoV-2 en forma leve. Sin embargo, de forma muy infrecuente algunos pueden desarrollar una patología con marcada gravedad denominada síndrome inflamatorio multisistémico en niños relacionado temporalmente con COVID-19 (SIM-C). Dado su reciente surgimiento, aún hay aspectos de su fisiopatología que se desconocen. La posibilidad de recidiva en caso de reinfección o ante la vacunación contra SARS-CoV-2 son nuevos interrogantes a los que nos enfrentamos. Reportamos una serie de casos de 4 pacientes adolescentes que cursaron SIM-C y meses después han sido vacunados contra SARS-CoV-2 con plataformas ARN mensajero (ARNm) sin presentar recurrencia de la enfermedad ni efectos adversos cardiológicos.

Better lipids to power next generation of mRNA vaccines.

New delivery systems aim to increase vaccine potency and reduce side effects.

Increased memory B cell potency and breadth after a SARS-CoV-2 mRNA boost.

The Omicron variant of SARS-CoV-2 infected many vaccinated and convalescent individuals1-3. Despite the reduced protection from infection, individuals who received three doses of an mRNA vaccine were highly protected from more serious consequences of infection4. Here we examine the memory B cell repertoire in a longitudinal cohort of individuals receiving three mRNA vaccine doses5,6. We find that the third dose is accompanied by an increase in, and evolution of, receptor-binding domain (RBD)-specific memory B cells. The increase is due to expansion of memory B cell clones that were present after the second dose as well as the emergence of new clones. The antibodies encoded by these cells showed significantly increased potency and breadth when compared with antibodies obtained after the second dose. Notably, the increase in potency was especially evident among newly developing clones of memory cells, which differed from persisting clones in targeting more conserved regions of the RBD. Overall, more than 50% of the analysed neutralizing antibodies in the memory compartment after the third mRNA vaccine dose neutralized the Omicron variant. Thus, individuals receiving three doses of an mRNA vaccine have a diverse memory B cell repertoire that can respond rapidly and produce antibodies capable of clearing even diversified variants such as Omicron. These data help to explain why a third dose of a vaccine that was not specifically designed to protect against variants is effective against variant-induced serious disease.

The indirect effect of mRNA-based COVID-19 vaccination on healthcare workers' unvaccinated household members.

Mass vaccination is effective in reducing SARS-CoV-2 infections among vaccinated individuals. However, it remains unclear how effectively COVID-19 vaccines prevent people from spreading the virus to their close contacts. Using nationwide administrative datasets on SARS-CoV-2 infections, vaccination records, demographics, and unique household IDs, we conducted an observational cohort study to estimate the direct and indirect effectiveness of mRNA-based COVID-19 vaccines in reducing infections among vaccinated healthcare workers and their unvaccinated household members. Our estimates for adults imply indirect effectiveness of 39.1% (95% CI: -7.1% to 65.3%) two weeks and 39.0% (95% CI: 18.9% to 54.0%) eight weeks after the second dose. We find that the indirect effect of mRNA-based COVID-19 vaccines within households is smaller for unvaccinated children than for adults and statistically insignificant. Here, we show that mRNA-based COVID-19 vaccines are associated with a reduction in SARS-CoV-2 infections not only among vaccinated individuals but also among unvaccinated adult household members in a real-world setting.

Opportunities and Challenges for mRNA Delivery Nanoplatforms.

With the global outbreak of SARS-CoV-2, mRNA vaccines became the first type of COVID-19 vaccines to enter clinical trials because of their facile production, low cost, and relative safety, which initiated great advances in mRNA therapeutic techniques. However, the development of mRNA therapeutic techniques still confronts some challenges. First, in vitro transcribed mRNA molecules can be easily degraded by ribonuclease (RNase), resulting in their low stability. Next, the negative charge of mRNA molecules prevents them from direct cell entry. Therefore, finding efficient and safe delivery technology could be the key issue to improve mRNA therapeutic techniques. In this Perspective, we mainly discuss the problems of the existing mRNA-based delivery nanoplatforms, including safety evaluation, administration routes, and preparation technology. Moreover, we also propose some views on strategies to further improve mRNA delivery technology.

Waning 2-Dose and 3-Dose Effectiveness of mRNA Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance - VISION Network, 10 States, August 2021-January 2022.

CDC recommends that all persons aged ≥12 years receive a booster dose of COVID-19 mRNA vaccine ≥5 months after completion of a primary mRNA vaccination series and that immunocompromised persons receive a third primary dose.* Waning of vaccine protection after 2 doses of mRNA vaccine has been observed during the period of the SARS-CoV-2 B.1.617.2 (Delta) variant predominance† (1-5), but little is known about durability of protection after 3 doses during periods of Delta or SARS-CoV-2 B.1.1.529 (Omicron) variant predominance. A test-negative case-control study design using data from eight VISION Network sites§ examined vaccine effectiveness (VE) against COVID-19 emergency department/urgent care (ED/UC) visits and hospitalizations among U.S. adults aged ≥18 years at various time points after receipt of a second or third vaccine dose during two periods: Delta variant predominance and Omicron variant predominance (i.e., periods when each variant accounted for ≥50% of sequenced isolates).¶ Persons categorized as having received 3 doses included those who received a third dose in a primary series or a booster dose after a 2 dose primary series (including the reduced-dosage Moderna booster). The VISION Network analyzed 241,204 ED/UC encounters** and 93,408 hospitalizations across 10 states during August 26, 2021-January 22, 2022. VE after receipt of both 2 and 3 doses was lower during the Omicron-predominant than during the Delta-predominant period at all time points evaluated. During both periods, VE after receipt of a third dose was higher than that after a second dose; however, VE waned with increasing time since vaccination. During the Omicron period, VE against ED/UC visits was 87% during the first 2 months after a third dose and decreased to 66% among those vaccinated 4-5 months earlier; VE against hospitalizations was 91% during the first 2 months following a third dose and decreased to 78% ≥4 months after a third dose. For both Delta- and Omicron-predominant periods, VE was generally higher for protection against hospitalizations than against ED/UC visits. All eligible persons should remain up to date with recommended COVID-19 vaccinations to best protect against COVID-19-associated hospitalizations and ED/UC visits.

SARS-CoV-2 Omicron Spike recognition by plasma from individuals receiving BNT162b2 mRNA vaccination with a 16-week interval between doses.

Continuous emergence of SARS-CoV-2 variants of concern (VOCs) is fueling the COVID-19 pandemic. Omicron (B.1.1.529) rapidly spread worldwide. The large number of mutations in its Spike raise concerns about a major antigenic drift that could significantly decrease vaccine efficacy and infection-induced immunity. A long interval between BNT162b2 mRNA doses elicits antibodies that efficiently recognize Spikes from different VOCs. Here, we evaluate the recognition of Omicron Spike by plasma from a cohort of SARS-CoV-2 naive and previously infected individuals who received their BNT162b2 mRNA vaccine 16 weeks apart. Omicron Spike is recognized less efficiently than D614G, Alpha, Beta, Gamma, and Delta Spikes. We compare with plasma activity from participants receiving a short (4 weeks) interval regimen. Plasma from individuals of the long-interval cohort recognize and neutralize better the Omicron Spike compared with those who received a short interval. Whether this difference confers any clinical benefit against Omicron remains unknown.

Vaccines to prevent COVID-19: A living systematic review with Trial Sequential Analysis and network meta-analysis of randomized clinical trials.

BACKGROUND: COVID-19 is rapidly spreading causing extensive burdens across the world. Effective vaccines to prevent COVID-19 are urgently needed. METHODS AND FINDINGS: Our objective was to assess the effectiveness and safety of COVID-19 vaccines through analyses of all currently available randomized clinical trials. We searched the databases CENTRAL, MEDLINE, Embase, and other sources from inception to June 17, 2021 for randomized clinical trials assessing vaccines for COVID-19. At least two independent reviewers screened studies, extracted data, and assessed risks of bias. We conducted meta-analyses, network meta-analyses, and Trial Sequential Analyses (TSA). Our primary outcomes included all-cause mortality, vaccine efficacy, and serious adverse events. We assessed the certainty of evidence with GRADE. We identified 46 trials; 35 trials randomizing 219 864 participants could be included in our analyses. Our meta-analyses showed that mRNA vaccines (efficacy, 95% [95% confidence interval (CI), 92% to 97%]; 71 514 participants; 3 trials; moderate certainty); inactivated vaccines (efficacy, 61% [95% CI, 52% to 68%]; 48 029 participants; 3 trials; moderate certainty); protein subunit vaccines (efficacy, 77% [95% CI, -5% to 95%]; 17 737 participants; 2 trials; low certainty); and viral vector vaccines (efficacy 68% [95% CI, 61% to 74%]; 71 401 participants; 5 trials; low certainty) prevented COVID-19. Viral vector vaccines decreased mortality (risk ratio, 0.25 [95% CI 0.09 to 0.67]; 67 563 participants; 3 trials, low certainty), but comparable data on inactivated, mRNA, and protein subunit vaccines were imprecise. None of the vaccines showed evidence of a difference on serious adverse events, but observational evidence suggested rare serious adverse events. All the vaccines increased the risk of non-serious adverse events. CONCLUSIONS: The evidence suggests that all the included vaccines are effective in preventing COVID-19. The mRNA vaccines seem most effective in preventing COVID-19, but viral vector vaccines seem most effective in reducing mortality. Further trials and longer follow-up are necessary to provide better insight into the safety profile of these vaccines.

Development and utilization of a surrogate SARS-CoV-2 viral neutralization assay to assess mRNA vaccine responses.

BACKGROUND: Tests for SARS-CoV-2 immunity are needed to help assess responses to vaccination, which can be heterogeneous and may wane over time. The plaque reduction neutralization test (PRNT) is considered the gold standard for measuring serum neutralizing antibodies but requires high level biosafety, live viral cultures and days to complete. We hypothesized that competitive enzyme linked immunoassays (ELISAs) based on SARS-CoV-2 spike protein's receptor binding domain (RBD) attachment to its host receptor, the angiotensin converting enzyme 2 receptor (ACE2r), would correlate with PRNT, given the central role of RBD-ACE2r interactions in infection and published studies to date, and enable evaluation of vaccine responses. METHODS AND RESULTS: Configuration and development of a competitive ELISA with plate-bound RBD and soluble biotinylated ACE2r was accomplished using pairs of pre/post vaccine serum. When the competitive ELISA was used to evaluate N = 32 samples from COVID-19 patients previously tested by PRNT, excellent correlation in IC50 results were observed (rs = .83, p < 0.0001). When the competitive ELISA was used to evaluate N = 42 vaccinated individuals and an additional N = 13 unvaccinated recovered COVID-19 patients, significant differences in RBD-ACE2r inhibitory activity were associated with prior history of COVID-19 and type of vaccine received. In longitudinal analyses pre and up to 200 days post vaccine, surrogate neutralizing activity increased markedly after primary and booster vaccine doses, but fell substantially, up to <12% maximal levels within 6 months. CONCLUSIONS: A competitive ELISA based on inhibition of RBD-ACE2r attachment correlates well with PRNT, quantifies significantly higher activity among vaccine recipients with prior COVID (vs. those without), and highlights marked declines in surrogate neutralizing activity over a 6 month period post vaccination. The findings raise concern about the duration of vaccine responses and potential need for booster shots.

SARS-CoV-2 mRNA vaccine induces robust specific and cross-reactive IgG and unequal neutralizing antibodies in naive and previously infected people.

Understanding vaccine-mediated protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is critical to overcoming the global coronavirus disease 2019 (COVID-19) pandemic. We investigate mRNA-vaccine-induced antibody responses against the reference strain, seven variants, and seasonal coronaviruses in 168 healthy individuals at three time points: before vaccination, after the first dose, and after the second dose. Following complete vaccination, both naive and previously infected individuals developed comparably robust SARS-CoV-2 spike antibodies and variable levels of cross-reactive antibodies to seasonal coronaviruses. However, the strength and frequency of SARS-CoV-2 neutralizing antibodies in naive individuals were lower than in previously infected individuals. After the first vaccine dose, one-third of previously infected individuals lacked neutralizing antibodies; this was improved to one-fifth after the second dose. In all individuals, neutralizing antibody responses against the Alpha and Delta variants were weaker than against the reference strain. Our findings support future tailored vaccination strategies against emerging SARS-CoV-2 variants as mRNA-vaccine-induced neutralizing antibodies are highly variable among individuals.