Category: Vaccine

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COVID-19 vaccination induces distinct T-cell responses in pediatric solid organ transplant recipients and … – Nature.com

April 6, 2024

Following on average one additional ancestral mRNA vaccine dose, pediatric solid organ transplant recipients do not exhibit significantly different humoral responses compared to their healthy siblings

Humoral responses were evaluated in pHCs and pSOTRs who received the ancestral monovalent vaccines only (pSOTR M) after approximately 200 days and pSOTR bivalent recipients (pSOTR B) after 300 days post-vaccination, just before the time at which boosting has been recommended for older adults and adult SOTRs due to waning immunity. The pSOTR M group received, on average one additional mRNA vaccine dose compared to pHCs (median three vs. two doses, respectively), while pSOTR B group received on average five mRNA vaccines, including the bivalent dose (Supplementary Table 1). Anti-S immunoglobulin (Ig)-G and anti-S1 receptor binding domain (RBD) IgG titers were not significantly different between pHCs and pSOTR groups (Fig. 1a). Interestingly, despite a previously documented infection in 11 (55%) pSOTR M, four (44%) pSOTR B, and five (50%) pHC participants, we observed no detectable anti-nucleocapsid (N) IgG in most individuals (Fig. 1b). While failure to acquire anti-N IgG following infection in children has not been reported, this is consistent with what has been observed in adults who were infected following vaccination22.

a Anti-S and anti-S1 RBD IgG titers in pHCs (n=10) and pSOTR monovalently vaccinated (M) (n=20) at approximately 6 months (180 days) since last vaccination and pSOTRs who received the bivalent dose (B) (n=8) 300 days post-vaccination. Squares denote individuals with history of COVID-19, circles represent no history of COVID-19. Darker shades of color indicate more vaccines received. KruskalWallis test, ns = not significant. b Anti-nucleocapsid IgG titers. The WHO cutoff of 12.3 units (positivity for natural infection) is depicted by dotted line. Filled circles represent individuals with self-reported or documented SARS-CoV-2 infection. c Percent ACE2 binding inhibition of ancestral strain and Omicron BA.5. Squares denote individuals with history of COVID-19, circles represent no history of COVID-19. Darker shades of color indicate more vaccines received. KruskalWallis tests, *p<0.05. The dotted line represents 25% ACE2 inhibition (limit of detection). d Correlations between anti-S IgG titers and ACE2 binding inhibition of ancestral strain and Omicron BA.5. e Matched pair percent ACE2 binding inhibition of ancestral strain vs. Omicron BA.5 for each individual within the groups. Wilcoxon matched-pairs rank test, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. f Anti-S and anti-S1 RBD IgG titers in pSOTR (n=8) six months since last vaccination and adult SOTRs (n=38) at peak vaccine responses (day 14). MannWhitney test, *p<0.05. g Percent ACE2 binding inhibition of ancestral strain and Omicron BA.5 in pSOTRs (n=8) and adult SOTRs (n=38). MannWhitney tests, *p<0.05. The dotted line represents 25% ACE2 inhibition (limit of detection). h Matched pair percent ACE2 binding inhibition of ancestral strain vs. Omicron BA.5 in pSOTRs (n=8) and adult SOTRs (n=38). Wilcoxon matched-pairs rank test, *p<0.05, ****p<0.0001. In (ac, f, g), boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values).

To assess antibody functionality, we measured percent angiotensin-converting enzyme 2 (ACE2) binding inhibition of the SARS-CoV-2 ancestral strain and Omicron BA.5 as a surrogate of neutralizing antibody function. This assay was previously validated in adult SOTRs23,24 and strongly correlated with live virus-neutralizing antibody titers in transplant recipients. Inhibition of the ancestral strain and BA.5 following monovalent vaccination was not significantly different between pSOTRs and pHCs; however, the pSOTR B group continued to exhibit slightly enhanced inhibition of Omicron BA.5 ten months post-vaccination (Fig. 1c). Although anti-S IgG titers positively correlated with ACE2 inhibition of both ancestral strain and Omicron BA.5 for all groups, there was a significant decrease in BA.5 surrogate neutralization compared to the ancestral strain, especially in monovalently vaccinated pHCs and pSOTRs (Fig. 1d, e).

Next, we compared antibody responses between pSOTR six months post-vaccination to 38 adult SOTRs two weeks post-third mRNA COVID-19 vaccine dose (i.e., peak response). To minimize heterogeneity, this analysis included only pSOTRs and adult SOTRs who were previously uninfected and who received three mRNA ancestral monovalent doses. pSOTRs six months post-vaccination exhibited significantly higher IgG titers (Fig. 1f) and greater neutralization capacity (Fig. 1g) compared to adult SOTRs at peak vaccine responses. Comparing percent inhibition of ancestral and Omicron BA.5 protein binding to ACE2 in the same individuals demonstrates that pSOTR and adult SOTRs had significantly lower BA.5 surrogate neutralization versus ancestral strain (Fig. 1h). Collectively, these data indicate that an additional mRNA vaccine dose in pSOTRs induced comparable IgG titers and neutralization capacity compared to immunocompetent children and that, despite waning, pSOTRs had significantly enhanced antibody responses six months post-vaccination compared to adult SOTRs at peak vaccine responses. Additionally, bivalent doses enhanced neutralization capacity against Omicron BA.5 in pSOTRs.

As anticipated, anti-S IgG antibody levels in pSOTRs significantly increased after the bivalent vaccination (day 14) compared to pre-vaccination (day 0), followed by a decline in responses approximately ten months later (day 300) (Fig. 2a). Given that monovalent vaccination was discontinued, it was not possible to determine if the same effect would be observed if the additional dose were not a bivalent vaccine. Three individuals in the bivalent group had matched pre- and post-bivalent dose samples. Anti-S IgG titers increased for all three, and anti-S1 RBD IgG titers increased for two out of the three individuals at day 14, before decreasing again at six months post-vaccination (Fig. 2b). Bivalently boosted pSOTRs also displayed a high capacity to neutralize both the ancestral strain and Omicron BA.5 at day 14 (Fig. 2c) in the surrogate neutralization assay. The three pSOTRs with matched pre- and post-bivalent dose samples all demonstrated a significant increase in ACE2 inhibition following the bivalent boost, especially for the BA.5 subvariant (Fig. 2d), including the child who did not demonstrate globally increased antibody titers (Fig. 2b, green star). Additionally, at day 14, bivalent recipients exhibited robust ACE2 binding inhibition of other Omicron subvariants, including BA.1, BA.2.75, BA.4.6, BF.7, and the more recently circulating BQ.1.1, BQ.1, and XBB.1, that was not significantly different from that of BA.5 surrogate neutralization (Fig. 2e). Importantly, no individuals had neutralizing capacity below the 25% ACE2 binding inhibition cutoff (previously shown to be specific for the presence of live-virus neutralization in SOTRs), suggesting overall excellent performance against Omicron subvariants. This suggests that not only are pSOTRs capable of effectively neutralizing Omicron BA.5, but also that an additional dose may help to protect this population from newly emerging SARS-CoV-2 variants. Ten months post-bivalent dose, pSOTRs exhibited decreased neutralizing capacity for every Omicron subvariant tested, with approximately half of individuals staying above the 25% cutoff (Fig. 2e). Lastly, while there was a positive correlation between anti-S IgG titers and ACE2 inhibition for both the ancestral strain and Omicron BA.5, decreased BA.5 inhibition was observed compared to the ancestral strain (Fig. 2f, g). Together, these findings provide evidence that either bivalent boosting or an additional mRNA vaccine dose significantly enhances antibody responses in pSOTRs, including increased total anti-SARS-CoV-2 IgG titers and improved surrogate neutralizing capacity against the ancestral strain, Omicron BA.5 and other variants of concern. However, anti-SARS-CoV-2 IgG titers and neutralizing capacities wane by ten months post-vaccination, suggesting that additional boosting might be beneficial in this population.

a Anti-S and anti-S1 RBD IgG titers in the pSOTR bivalent group at days 0 (D0; pre-bivalent) (n=4), 14 (D14; peak responses) (n=9) and 300 (D300; waning responses) (n=8). KruskalWallis test, *p<0.05, **p<0.01. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). b Anti-S and anti-S1 RBD IgG titers at days 0, 14, and 300 since the bivalent vaccination in three individuals with matched plasma samples. c Percent ACE2 binding inhibition of ancestral strain and Omicron BA.5 in bivalent vaccine pSOTR recipients. KruskalWallis tests, *p<0.05, **p<0.01, ***p<0.001. The dotted line represents 25% ACE2 inhibition (limit of detection). Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). d Percent ACE2 binding inhibition of the ancestral strain and Omicron BA.5 at days 0, 14, and 300 since the bivalent vaccination in three individuals with matched plasma samples. e Percent ACE2 binding inhibition of the ancestral strain and Omicron variants of concern (VOC) in bivalent dose recipients at peak (left) and day 300 (right). A single individual was infected between days 14 and 300 (red circles). Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). f Correlations between anti-S IgG titers and ACE2 binding inhibition of ancestral strain and Omicron BA.5 at peak responses (see Fig. 1d for correlations at day 300). g Matched pair percent ACE2 binding inhibition of ancestral strain vs. Omicron BA.5 at days 0 and 14 (see Fig. 1e for day 300). Wilcoxon matched-pairs rank test, **p<0.01.

Although 22% of the U.S. pediatric population has reported a positive COVID-19 test since the beginning of the COVID-19 pandemic, infection seroprevalence could be as high as 96%21,25. In this cohort, approximately 50% of participants in each group reported an infection (Supplementary Table 1). Given the frequency of pediatric infection in the U.S. and that little is known about SARS-CoV-2 vaccine immunity in pSOTRs since the Omicron variant emerged, we stratified antibody responses by COVID-19 infection status (Supplementary Table 1).

One individual in the pSOTR group had COVID-19 twice and one of the infections occurred when Omicron BA.5 was circulating. All other study participants were infected between May 2021 and June 2022 (i.e., before Omicron BA.5 became the dominant variant in the U.S.). There were no significant differences in total IgG titers and ancestral or BA.5 surrogate neutralization between vaccinated uninfected and vaccinated infected individuals within each group (Supplementary Fig. 1a, b). This suggests that the antibody results likely reflect vaccine-induced rather than infection-induced or hybrid immune responses.

To examine S antigen-specific T cells induced by ancestral monovalent vaccination and vaccination plus infection, participant PBMCs were stimulated with overlapping ancestral (W.1) and Omicron BA.4/5 S protein peptides. Subsequently, the production of interferon (IFN)-, tumor necrosis factor (TNF), interleukin (IL)-2, and IL-21 cytokines was assessed by flow cytometry (Fig. 3a, b). As with antibody responses, no significant differences in CD4+ T-cell responses were observed between uninfected vaccinated participants and those vaccinated and previously infected (Supplementary Fig. 2). In contrast to the antibody responses, pSOTRs and pHCs vaccinated with monovalent mRNA vaccines exhibited no significant differences in the frequency of CD4+ T-cell responses recognizing Omicron BA.5 epitopes compared to the ancestral strain (Fig. 3c). Interestingly, despite receiving one fewer vaccine dose on average than the pSOTR M group and more than two fewer doses on average than the pSOTR B group, pHCs demonstrated greater production of IFN- by S-specific CD4+ T cells in response to both ancestral and BA.4/5 peptides (Fig. 3d). This result remained significant after accounting for prior COVID-19 infection, immunosuppression (mycophenolate mofetil use), liver transplant history, age, number of vaccines received, and time between vaccination and sample collection (Supplementary Table 2). Production of other cytokines was not statistically significantly different between pSOTRs and pHCs six months post ancestral vaccination or pSOTRs ten months post bivalent dose. However, compared to three times vaccinated uninfected adult SOTRs at peak vaccine response26, three-times vaccinated and uninfected pSOTRs produced significantly more IFN-, IL-2, and TNF in response to ancestral S protein stimulation, and TNF in response to BA.4/5 S protein stimulation six months post-vaccination (Fig. 3e). In sum, while immunocompetent children produced significantly more IFN- in response to S peptide stimulation, pSOTRs showed comparable production of all other cytokines and greater production of most cytokines assessed six months post-vaccination compared to adult SOTRs at peak responses.

a Representative flow cytometry gating of cytokine-producing S-specific CD4+ T cells. b Representative cytokine production by S-specific CD4+ T cells unstimulated (baseline) or stimulated with ancestral (W.1) or Omicron BA.4/5S protein peptides. c Cytokine production by S-specific CD4+ T cells in responses to ancestral and BA.4/5S peptides in pSOTRs and pHCs vaccinated with monovalent mRNA COVID-19 vaccines. One-way ANOVA with Tukey correction, ns = not significant. d Frequencies of cytokine-producing S-specific CD4+ T cells in response to BA.4/5 or ancestral S peptide stimulation. Squares denote individuals with history of COVID-19, circles represent no history of COVID-19. Darker shades of color indicate more vaccines received. Two-way ANOVA with Tukey correction for multiple comparisons, **p<0.01. An = ancestral strain. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). e Frequencies of cytokine-producing S-specific CD4+ T cells in response to BA.4/5 or ancestral S peptides in pSOTRs (n=8) six months since the last vaccine dose and adult SOTRs (n=19) for which we had PBMC samples at peak vaccine responses (day 14). Two-way ANOVA with Tukey correction, *p<0.05, **p<0.01. An = ancestral strain. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values).

Bivalent boosting in pSOTRs enhanced CD4+ T-cell production of IFN- and TNF following ancestral S peptide stimulation compared to days 0 and 300, and IL-21 compared to day 300 (Fig. 4a). Similarly, bivalent recipients exhibited improved production of IFN- and TNF in response to BA.4/5 peptides compared to days 0 and 300 (Fig. 4a). This suggests that memory CD4+ T cells in pSOTRs can be boosted and successfully recalled following additional mRNA vaccine doses and/or the bivalent dose, but wane over time to pre-bivalent levels. Two out of three matched bivalent recipients exhibited increased CD4+ T-cell responses following bivalent boosting in response to both ancestral and BA.4/5 peptides (Fig. 4b, c). Interestingly, IFN- production increased in one individual in response to ancestral peptide, and two individuals in response to BA.4/5 peptides, however, neither had a reported SARS-CoV-2 infection between days 14 and 300 post-vaccination. There were no differences in the frequency of CD4+ T-cell responses recognizing ancestral and Omicron BA.4/5 epitopes in pSOTRs bivalent recipients at days 0, 14, and 300 (Fig. 4d). Overall, bivalent boosting in pSOTRs led to an enhanced cytokine production by CD4+ T cells at peak with conserved recognition of ancestral strain and BA.4/5 peptides. CD4+ T-cell cytokine production waned over time, which is in contrast with cytokine production observed in immunocompetent children after two to three doses of ancestral monovalent vaccines (Fig. 3).

a Frequencies of cytokine-producing S-specific CD4+ T cells in response to BA.4/5 or ancestral S peptides at 0, 14, and 300 days post-bivalent vaccination. Two-way ANOVA with Tukey correction, *p<0.05, **p<0.01. An = ancestral strain. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). b, c Cytokine production by S-specific CD4+ T cells in response to BA.4/5 or ancestral S peptides for three pSOTR individuals with matched PBMC samples at 0, 14, and 300 days post-bivalent vaccination. d Cytokine production by S-specific CD4+ T cells in responses to ancestral and BA.4/5 S peptides at days 0, 14, and 300 post-bivalent vaccination. One-way ANOVA with Tukey correction, ns = not significant.

Live attenuated and viral vector-based vaccines have traditionally elicited strong CD8+ T-cell responses, which may offer additional protection independent of antibody responses27,28,29. Although mRNA vaccine-induced S-specific CD8+ T-cell responses in pSOTRs have not been comprehensively characterized, studies in adult SOTRs have reported limited CD8+ T-cell responses26,30. For both pSOTRs and pHCs, the overall frequency of cytokine producing CD8+ T cells upon stimulation with ancestral or Omicron BA.4/5 peptides remained low, often comparable to background (S peptide unstimulated) levels (Fig. 5ac). Furthermore, at six months post bivalent dose, pSOTRs exhibited limited cytokine production by S-specific CD8+ T cells (Fig. 5c). Bivalent boosting slightly improved CD8+ T-cell production of IFN- and TNF at peak vaccine responses, but not significantly (Fig. 6ad). Overall, cytokine production by CD8+ T cells was limited, demonstrating that mRNA COVID-19 vaccines induce more robust CD4+ than CD8+ T-cell responses in pediatric populations.

a Representative cytokine production by S-specific CD8+ T cells unstimulated (baseline) or stimulated with ancestral (W.1) or Omicron BA.4/5 S protein peptides. b Cytokine production by S-specific CD8+ T cells in response to ancestral and BA.4/5S peptides in monovalently vaccinated pSOTRs and pHCs. One-way ANOVA with Tukey correction, ns = not significant. c Frequencies of cytokine-producing S-specific CD8+ T cells in response to BA.4/5 or ancestral S peptides. Two-way ANOVA with Tukey correction. An = ancestral strain. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values).

a Frequencies of cytokine-producing S-specific CD8+ T cells in response to BA.4/5 or ancestral S peptides in pSOTRs at days 0, 14, and 300 post-bivalent dose. Two-way ANOVA with Tukey correction. An = ancestral strain. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). b, c Cytokine production by S-specific CD8+ T cells in response to BA.5 or ancestral S peptides for three pSOTR individuals with matched PBMC samples at days 0, 14, and 300 post-bivalent dose. d Cytokine production by S-specific CD8+ T cells in response to ancestral and BA.4/5S peptides in pSOTRs bivalent recipients at days 0, 14, and 300 post-bivalent dose. One-way ANOVA with Tukey correction, ns = not significant.

Early studies reported that SARS-CoV-2 infection induces robust CD8+ T-cell responses in adults31,32. Hence, we stratified CD8+ T-cell responses by previous history of COVID-19. Comparable to CD4+ T-cell and antibody results, CD8+ T-cell responses were not significantly different between those with and without a history of SARS-CoV-2 infection (Supplementary Fig. 3). Additionally, as mentioned previously, all cytokines tested were present in very low frequencies preventing trend evaluation in each group. These results further confirm that the responses we observed were induced mainly by vaccination and that S-specific CD8+ T-cell responses were low compared to CD4+ T-cell responses.

Polyfunctionality is defined as the ability of T cells to produce more than one cytokine simultaneously and has been associated with protection in previous studies against other infections33,34. Due to overall low CD8+ T-cell responses (Figs. 5, 6), we evaluated polyfunctionality in CD4+ T cells only. Ancestral and BA.4/5 peptide stimulation induced no significant difference in overall frequencies of S-specific polyfunctional CD4+ T cells within each group (Fig. 7a). However, pHC participants demonstrated increased polyfunctionality in response to ancestral and BA.4/5S peptide stimulation compared to the pSOTR groups (Fig. 7b, c), primarily due to increased simultaneous production of TNF and IFN- (category 6, purple). Additionally, S-specific CD4+ T cells in pHCs produced significantly more IFN- only (category 8, orange), while pSOTR CD4+ T cells produced more TNF only in response to both ancestral and BA.4/5 peptides (category 14, dark pink) (Fig. 7c). Together, these findings suggest that while pSOTRs produce polyfunctional CD4+ T cells in response to mRNA vaccination, they are qualitatively different compared to polyfunctional CD4+ T cells produced by immunocompetent children, and lack robust production of IFN-.

a Ancestral and BA.4/5 peptide stimulation induced no significant differences in frequencies of polyfunctional CD4+ T cells in each group. Pie charts are broken down by the 15 cytokine combination categories. Arcs identify slices of the pie that express each specific cytokine. b Heatmap identifying absolute differences between groups for each category (115). c Frequencies of CD4+ T cells producing cytokine combinations in response to ancestral or BA.4/5 peptides. Two-way ANOVA with Tukey correction, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Error bars represent standard error of the mean.

We next assessed S-specific CD4+ T-cell polyfunctionality and whether an additional dose of vaccine could increase IFN- production by pSOTRs (Fig. 8). We did not observe significant differences in ancestral or BA.4/5-induced cytokine production (Fig. 8a), but overall polyfunctionality was significantly improved shortly after post-bivalent vaccination (Fig. 8b, c). Bivalent boosting primarily increased the frequency of CD4+ T cells simultaneously producing IL-2 and TNF (category 10, green) in response to BA.4/5S peptides at peak responses. Additionally, the production of IFN- only (category 8, orange), IL-2 only (category 12, dark blue), and TNF only (category 14, dark pink) significantly increased at peak compared to prior and ten months post-bivalent boosting (Fig. 8b, c). In sum, bivalent boosting enhances IFN- production by CD4+ T cells 14 days post-vaccination, but not long-term, as seen in pHCs. Instead, bivalent doses in pSOTRs enhanced long-term TNF and IL-2 cytokine production (Figs. 7c, 8c).

a Cytokine production by CD4+ T cells in response to ancestral and Omicron BA.4/5 peptides at days 0, 14, and 300 post-bivalent vaccination. Pie charts depict the 15 cytokine combination categories. Arcs identify slices of the pie that express each specific cytokine. b Heatmap identifying absolute differences between groups for each category. c Frequencies of CD4+ T cells producing cytokine combinations in response to ancestral or BA.4/5 peptide stimulation. Two-way ANOVA with Tukey correction, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Error bars represent standard error of the mean.

Subsequently, we investigated whether CD4+ T-cell polyfunctionality differs in the nine pSOTR bivalent recipients depending on history of COVID-19 (Supplementary Fig. 4). While infected individuals tended to exhibit slightly increased production of IFN- (category 8) and TNF (category 14), no significant differences in cytokine production or polyfunctionality between individuals with or without previously documented SARS-CoV-2 infection were noted (Supplementary Fig. 4a, b), further indicating that the responses observed in this study are predominantly vaccine-induced.

We then comprehensively evaluated phenotypic and functional markers of S-specific CD4+ T cells induced in response to ancestral and BA.4/5 peptides using high parameter flow cytometry. The panel includes 29 surface and intracellular markers designed to evaluate T-cell subsets, metabolism, activation, and exhaustion phenotypes (Supplementary Table 3). No significant differences in S-specific CD4+ T-cell phenotypes were observed between responses to the ancestral (Supplementary Fig. 5) and BA.4/5 peptides (Fig. 9). Therefore, the subsequent analysis represents the response to BA.4/5 peptide stimulation.

a UMAP dimension reduction plot for each group. b Unsupervised clustering algorithm Xshift identified 8 clusters on the UMAP. c Heatmap of normalized mean fluorescent intensity (MFI) values of markers expressed in each cluster. d Frequency of clusters in each group. Two-way ANOVA with Tukey correction, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Error bars represent standard error of the mean. e MFI plots for significant clusters determined in (d), ungated clusters (gray) and bulk T cells (black).

The uniform manifold approximation and projection (UMAP) revealed significant differences in S-specific CD4+ T-cell phenotypes, especially between the transplant recipient groups and pHCs (Fig. 9a). The unsupervised clustering algorithm that uses k-nearest neighbors density estimation, Xshift35, was then applied, and identified eight distinct S-specific CD4+ T-cell clusters on the UMAP (Fig. 9b). The mean fluorescent intensities (MFIs) of markers expressed in each cluster are depicted in Fig. 9c. The frequencies of three clusters (6, 7, and 8) were statistically significantly different among the groups (Fig. 9d, e). Clusters 6 and 7 were enriched in the pHC group compared to the transplant recipient groups (Fig. 9d). Cells in these two clusters were metabolically active (GLUT1+, PD-1+), and expressed comparatively very high levels of IFN- (Fig. 9e). Cluster 7 cells were more polyfunctional than cluster 6 cells, expressing high frequencies of all four cytokines. Clusters 6 and 7 also expressed CD27 and CD28, consistent with a functional memory T-cell phenotype. Monovalently and bivalently vaccinated pSOTRs had the highest frequency of S-specific CD4+ T cells in cluster 8 (Fig. 9d, e). Cluster 8 cells expressed high levels of cytokines TNF and IL-2, but very little IFN- compared to other clusters (Fig. 9e). This is consistent with our polyfunctionality results in which pSOTR bivalent recipient CD4+ T cells co-expressed TNF and IL-2 (Fig. 8). Similar to clusters 6 and 7, cluster 8 cells expressed CD27, CD28, PD-1 and GLUT1, indicative of activated and functional memory T-cell phenotype.

We then applied the same analytical pipeline to cells from bivalent recipients prior to boosting, at peak and ten months post-vaccination. Again, no significant differences in S-specific CD4+ T-cell phenotypes were observed between responses to the ancestral (Supplementary Fig. 6) and BA.4/5 peptides (Fig. 10). The UMAP revealed slight differences in S-specific CD4+ T-cell phenotypes (Fig. 10a), especially expression of various cell markers on day 14 compared to days 0 and 300, and Xshift then identified seven S-specific CD4+ T-cell clusters on the UMAP (Fig. 10b). MFIs of markers expressed in each cluster are depicted in Fig. 10c. All seven clusters were present in comparable frequencies in each group (Fig. 10d).

a UMAP dimension reduction plot for each group. b Unsupervised clustering algorithm Xshift identified 7 clusters on the UMAP. c Heatmap of normalized mean fluorescent intensity (MFI) values of markers expressed in each cluster. d Frequency of clusters in each group. Two-way ANOVA with Tukey correction, all not significant. Error bars represent standard error of the mean.

Overall, our analysis of S-specific CD4+ T cells induced in response to BA.4/5 peptide stimulation suggests that despite immunosuppression, pSOTR recipients can generate metabolically active S-specific CD4+ T cells that are qualitatively distinct, primarily producing TNF and IL-2, less IL-21 and very little IFN- relative to pHCs. T cells of this phenotype were enhanced following bivalent vaccination, demonstrating that bivalent vaccination did not result in a higher proportion of T cells producing IFN-. This is distinct from CD4+ T cells generated in pHCs that were also metabolically active but mostly produced IFN-. Since monovalent pSOTR recipients produce similar frequencies of IFN--producing CD4+ T cells as bivalent recipients, we hypothesize that immunosuppressive regimens alter the S-specific CD4+ T-cell compartment rather than that IFN- production is associated with fewer vaccine doses.

Finally, we performed T-cell proliferation assay to further assess T-cell responses following vaccination (Fig. 11a). Cell trace violet dye-labeled PBMCs were cultured for five days in the presence of ancestral S peptides to drive the proliferation of S-specific T cells. Individuals who received bivalent vaccination exhibited the highest proliferation 14 days post-vaccination, as expected (Fig. 11b, c). Surprisingly, the pHC and pSOTR groups showed comparable S-specific T-cell proliferation at the time of waning immunity, potentially because children generally require lower doses of immunosuppressive regimes compared to adults. Interestingly, S-specific CD8+ T cells exhibited remarkable proliferation despite limited cytokine production. We then correlated CD4+ T cells proliferation with cytokine production and found a strong correlation between cytokine production and CD4+ T-cell proliferation in healthy children, but this correlation was not observed in pSOTRs (Fig. 11d). This further suggests that cytokine production and proliferation of S-specific CD4+ T cells is dysregulated in pSOTRs.

a Representative gating of cell trace violet-labeled, S-specific, proliferating daughter T cells in response to ancestral SARS-CoV-2 S peptides. b Proliferating S-specific CD4+ and CD8+ T cells (% memory) in pHC, pSOTR M, and pSOTR B groups at the time of waning immunity. No significant relationships. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). c Proliferating CD4+ and CD8+ T cells (% memory) in pSOTR B at days 0, 14, and 300. Kruskal-Wallis test, *p<0.05, ns = not significant. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). d Heatmap depicting correlations between proliferation of S-specific CD4+ T cells and cytokine production in pHCs and pSOTRs. The cytokine category combines TNF, IL-21, IL-2, and IFN- production. Pearson correlation coefficients are depicted in each square. Higher coefficient represents greater correlation.

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COVID-19 vaccination induces distinct T-cell responses in pediatric solid organ transplant recipients and ... - Nature.com

MSU experts speak to measles outbreak and the science and hesitancy of vaccinations – MSUToday

April 6, 2024

It takes only one case of measles or other vaccine-preventable diseases for an outbreak to begin. In fact, in 2023 measle cases were up 80%, according to a TIME Magazine report, and the Michigan Department of Health and Human Services reported the first case of measles for the state this year in February.

But vaccines can prevent or lessen the severity of the condition in question for everyone, according to Peter Gulick, professor of Osteopathic Medical Specialties at the Michigan State University College of Osteopathic Medicine.

Unfortunately, disinformation and fear cause people to choose not to vaccinate themselves or their children, Gulick said. Its the reduction in immunity over time, and then all you need is one case, and then if it hits other people who dont have immunity, it spreads.

Some of that misinformation has included a paper published linking the mumps/measles/rubella, or MMR, vaccine that protects against measles to autism. That was found to be a totally false article it was retracted, and the publisher said there is no evidence, the data was put together wrong. But people still bring it up, Gulick explained.

Sean Valles, professor and director of the MSU College of Human Medicines Center for Bioethics and Social Justice suggests listening to those who are reluctant to get vaccinated and address their concerns.

Vaccine hesitancy, he said, includes concern about potential side effects, a false belief that a vaccine can cause the disease it is supposed to protect against, unfounded rumors and distrust of medical science fed by Internet conspiracies, and even a fear of needles. Most vaccine skeptics are not completely opposed to vaccination, Valles said.

In the case of measles, it is so contagious, far and away more than almost anything else, Valles said, that we dont have room for error.

The MMR vaccine has been available and highly effective in preventing the deadly disease since the early 1970s, lulling some parents into a false sense of security that measles has been eradicated, although, in fact, it never left. Other parents fall prone to a highly politicized climate of misinformation.

Vaccine hesitancy has sort of always been there, Valles said, but its become much more organized.

There are always going to be those people who are going to be a hard no, he added, no matter what you say.

The key, he said, is to find those who remain at least partially open-minded.

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MSU experts speak to measles outbreak and the science and hesitancy of vaccinations - MSUToday

Message by the Director of the Department of Immunization, Vaccines and Biologicals at WHO – March 2024 – World Health Organization (WHO)

April 6, 2024

Kate O'Brien, Director of the Department of Immunization, Vaccines and Biologicals at WHO

In a pivotal meeting last month, the Strategic Advisory Group of Experts on Immunization (SAGE) came together to examine comprehensive global and regional reports on immunization programme and outbreak status on immunization programme and outbreak status, thoroughly explore the progress on Immunization Agenda 2030 (IA 2030) goals, and offer vital recommendations regarding polio, hepatitis E, and Mpox vaccines.

The meeting also celebrated the 50th anniversary of the Expanded Programme on Immunization (EPI), recognizing its monumental achievements since its founding in 1974, while charting a course for its future endeavors. Over the past five decades, immunization has emerged as a cornerstone of primary healthcare, community development, and global health, by significantly impacting child survival rates through largescale prevention of vaccine-preventable disease and mortality. EPI has not only created the foundations of primary healthcare in many countries but has also played a vital role in promoting equity in healthcare access.

The meeting highlighted the remarkable advancements in vaccine technologies and distribution mechanisms, which have led to the development and deployment of numerous life-saving vaccines.

However, amidst the celebration of past accomplishments, SAGE also acknowledged recent setbacks, particularly in meeting the goals outlined in the IA 2030. While preliminary data from 2023 show increasing signs of recovery towards pre-pandemic vaccination levels, there remains much work to be done to realign efforts with the Agendas objectives. Looking ahead, SAGE emphasized the importance of country ownership, community-centered approaches, partnership building, and data-driven decision-making without which the goals of IA 2030 will not be achieved.

The meeting also addressed the implementation progress of the Big Catch-up initiative, stressing the necessity of political commitment, community involvement, and healthcare workforce capacity building. Monitoring the initiative's progress through robust data collection and analysis was deemed essential for informing future actions and ensuring accountability. Recognizing the challenges in data collection and surveillance systems, SAGE emphasized the need for long-term investments in strengthening immunization data capacity and infrastructure.

As the world continues to navigate health challenges and polycrises, SAGE reaffirmed its commitment to advancing immunization efforts worldwide, guided by evidence-based strategies and a collective resolve to safeguard public health.

EYE Strategy Annual Partners' Meeting 2024

The convening served as a platform to commend and extend support to Ethiopia for its recent decision to incorporate the yellow fever vaccine into its routine immunization schedule nationwide, a strategic move aimed at bolstering the country's defenses against this potentially devastating disease. Additionally, the gathering aimed to strategize and mobilize resources for the implementation of preventive mass vaccination campaigns, crucial steps in curbing the spread of yellow fever.

Amidst discussions and exchanges of insights, the meeting celebrated a monumental achievement: the protection of more than 365 million individuals across Africa against yellow fever since the inception of the EYE Strategy. Of these, over 264 million people have been safeguarded through extensive vaccination campaigns, underscoring the efficacy and impact of concerted efforts in disease prevention and control.

However, the convening also shed light on the sobering reality of the resurgence of yellow fever outbreaks in regions that have historically benefited from preventive mass vaccination campaigns. Comprehensive analyses were presented, prompting a collective commitment among partners and stakeholders to implement catch-up interventions and strengthen routine immunization programs for yellow fever vaccination and beyond.

Furthermore, partners and key stakeholders reflected on the EYE Strategy's trajectory, recognizing that it has entered an accelerated phase following an independent mid-term evaluation. This phase necessitates a renewed and intensified commitment from all involved parties to ramp up activities related to yellow fever prevention and control until the Strategy's formal conclusion in 2026.

The EYE Strategy Annual Partners' Meeting 2024 underscored the importance of proactive measures, solidarity among nations, and sustained investment in public health initiatives to safeguard communities worldwide from the life-threatening consequences of infectious diseases.

Measles and Rubella Partnership ignites action

The Measles and Rubella Partnership (M&RP) also held a series of leadership and partnership meetings in Washington DC in March, with a focus on achieving a measles and rubella-free world. Over 150 global participants gathered for the first time since 2019, to ignite discussions on breaking through bottlenecks, broaden horizons, and tackle challenges head-on in pursuit of the strategy goals for measles and rubella elimination.

The meeting concluded with a call-to-action, urging increased ownership and collaboration, proactive efforts to close immunity gaps, adoption of innovative approaches, amplified investments in cutting-edge technologies, and a commitment to sustaining and accelerating our collective efforts towards achieving our measles and rubella eradication goals.

With determination, the M&RP community marches forward, fueled by the belief that together, we can build a world free from the threat of measles and rubella.

For the first time, cervical cancer's end is in sight

March brought monumental progress in the fight against cervical cancer, signaling that the end of this deadly disease is finally within sight. The first-ever "Global cervical cancer elimination forum: advancing the call to action" held from March 5th to 7th, in Cartagena de Indias, Colombia, served as a game-changing platform. Governments, donors, multilateral institutions, and partners converged to champion the global elimination strategy and address the stark inequities denying women and girls access to life-saving interventions.

Despite having all the necessary tools to prevent and eliminate cervical cancer, the disease continues to wreak havoc on hundreds of thousands of women, families, and communities worldwide. Access to vaccines, screening, and treatment remains woefully inadequate in the most vulnerable regions. Vaccines, crucial in preventing human papillomavirus (HPV) infections and subsequently cervical cancer, are not reaching those who need them the most.

However, hope soared as unprecedented commitments were announced at this landmark forum, totaling nearly US$600 million in new funding to eradicate cervical cancer. These commitments, aimed at expanding vaccine coverage and strengthening screening and treatment programs, could potentially mark the first-ever elimination of a cancer. This momentum builds upon the promise made in 2020 when 194 countries adopted WHO's global strategy to eliminate cervical cancer.

With bold commitments and decisive action, the focus now shifts to accelerating progress and supporting countries in their journey towards equitable access to care. Together with partners, efforts are underway to pave the way for a future where all women, regardless of socio-economic status or geographic location, have access to the care they deserve.

Combatting malaria: a call to action in Africa's high-burden countries

Despite progress, malaria continues to claim lives and devastate families, with the African region bearing the brunt of the burden, representing 94% of global malaria cases and 95% of global deaths.

The conference culminated in the signing of a declaration by ministers committing to stronger leadership and increased domestic funding for malaria control programs. The pledge includes further investment in data technology, application of latest technical guidance, and enhancement of efforts at national and sub-national levels.

To reignite progress against malaria, greater domestic and international funding, science-driven responses, research, and innovation are imperative. With political leadership, country ownership, and collaborative partnerships, the story of malaria in Africa can be rewritten for the betterment of families and communities continent-wide

April's global health milestones: promoting immunization efforts

April is set to host two significant events aimed at advancing global health initiatives and promoting immunization efforts.

Firstly, WHO is gearing up for its inaugural high-level meeting to combat meningitis. Scheduled to take place in Paris on April 26, this meeting aims to mobilize commitments towards achieving the objectives outlined in the WHO Global Road Map to defeat meningitis by 2030. With a focus on galvanizing support and resources, the meeting signals a crucial step towards eliminating meningitis epidemics and caring for those who suffer the long-term consequences of meningitis.

Additionally, April 24-30 will see the celebration of World Immunization Week, a rallying call to ramp up investments in immunization programs, and in so doing, ensuring the protection of future generations against deadly infections. The central theme this year will be the 50th anniversary of the EPI, highlighting the commitment of the global community to prioritize public health and strengthen immunization efforts, underscoring the importance of collective action in achieving health equity and resilience. The theme this year will be Humanly Possible and we welcome all of you to plan for how you will mark this week and contribute to the social movement of immunization. Please visit the World Immunization Week 2024 portal where all the social media assets and more information on activities during the week will be available by mid-April. Take part, join in, and add your voice.

By building on the foundation of past successes, we can assure that vaccines continue to save ever more lives each year. Through sustained investment, collaboration, and a shared commitment to vaccines and immunization programmes, we can harness the full potential of these life-saving products to protect individuals, communities, and future generations from preventable diseases.

Let us take this unique moment of 50 years of country immunization programmes to reaffirm the evidence on their crucial role in the health of people across all ages and especially their role to protect the adult in every child.Vaccines have an indispensable role in safeguarding human health and well-being worldwide.

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Message by the Director of the Department of Immunization, Vaccines and Biologicals at WHO - March 2024 - World Health Organization (WHO)

Investing in Vaccines is a No-Brainer – Precision Vaccinations

April 6, 2024

(Precision Vaccinations News)

According to an article written byAdam Tooze, in a world of polycrisis, in which intersecting problems compound each other and there are few easy wins, it is all the more important to recognise those policy choices that are truly obvious.

Funding vaccine development isone such investment.

Published by The Financial Times on April 1, 2024, this opinion article says modest expenditures on public health have saved tens of millions of lives, reduced morbidity, and allowed children around the world to develop into adults capable of living healthy and productive lives.

The complete, unedited article is posted at this link.

Originally posted here:

Investing in Vaccines is a No-Brainer - Precision Vaccinations

Alabama bill regarding vaccine religious exemptions heads to senate floor – WIAT – CBS42.com

April 6, 2024

MONTGOMERY, Ala. (WIAT) Every year, Alabama students must stay up to date on their vaccinations. One lawmaker said that the government can only do so much when it comes to religious beliefs.

Under current Alabama law, parents must receive written notice from the county health department to exempt their child from a vaccination. State Sen. Arthur Orrs (R-Decatur) bill to change the current vaccine exemption policy was passed by the Senate Education Policy Committee.

The bill mandates written statements from parents as the only documentation needed to get exemptions. Orr said hes heard concerns from many of his constituents.

Ive received complaints from parents saying Well, I went to the county health department. I waited for an hour or two to see the right person, then I had a government bureaucrat start questioning me about why I have certain religious beliefs,' Orr said.

But Dr. Nola Ernest, president of the Alabama Chapter of the American Academy of Pediatrics, said children might get diseases that are preventable as a result of this bill.

For pediatricians, our reaction to increasing religious and philosophical exemptions for vaccines is a little bit one of fear, Ernest said. Many of us have not practiced in a time where vaccine preventable diseases were rampant.

Orr said the bill is about parents right to religious exemptions.

But we need to take the government out of the process as far as determining, or probing, ones religious beliefs, Orr said.

After passing through the committee, the bill now heads to the floor for a vote.

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Alabama bill regarding vaccine religious exemptions heads to senate floor - WIAT - CBS42.com

Potent and long-lasting humoral and cellular immunity against varicella zoster virus induced by mRNA-LNP vaccine … – Nature.com

April 6, 2024

gE antigen design, expression, and characterization

Since glycoprotein E (gE) is the most abundantly expressed antigen both on the surface of the varicella zoster virus (VZV) particles and on the infected cells24 and is used in the currently approved subunit vaccine Shingrix16, we therefore designed our mRNA constructs to encode this protein. gE is a transmembrane protein consisting of a long N-terminal extracellular domain expressed on the cell or viral surface, a short transmembrane domain anchoring the protein to the viral or host cell membrane, and a short C-terminal cytoplasmic domain. The N-terminal extracellular domain mediates its binding to insulin-degrading enzyme (IDE) on the cell surface26 and represents the main VZV antigen for recognition by antibodies and T-cells. The C-terminal domain has been shown to play a critical role in gE protein localization, however, the relationship between localization of the membrane protein and immunity is poorly understood. Therefore, our experimental designs for selection of a particular gE antigen-encoding mRNA candidate were based on comparison of the full-length gE antigen to its truncated variants. Specifically, we designed three versions of the gE antigen (Fig. 1A): (i) full-length gE (gE full-length), as present on the surface of the virion or naturally infected cells24, (ii) truncated gE (gE truncated), generated by deleting a part of the C-terminal domain and including a single amino acid substitution (Y569A) altering one of the trans-Golgi network (TGN) localization motifs, as described previously25, and (iii) soluble gE (gE-soluble), which is expressed as the extracellular domain of the protein and similar to the antigen sequence in Shingrix. In truncated gE, the C-terminal domain containing the trans-Golgi network (TGN) localization motif was modified by a single point-mutation: AYRV to AARV (Y569A). These modifications were made in truncated gE with the aim to address gE trafficking and thus potentially improve the surface expression of gE after translation. In addition to a codon-optimized open reading frame, the mRNA also contained a proprietary transcription initiation sequence (TIS), human -globin (HBG) 5 UTR and 3 UTR sequences, and a polyA tail sequence. The final transcript was 5 capped and contained N1-methylpseudouridine (m1) modified bases.

A Schematic representation of the various domains of VZV gE. The N-terminal domain contains disulfide bonds, N-glycans, and O-glycans (O-glycans not shown). Three versions of the VZV gE protein that we designed are shown: The soluble gE protein (gE soluble) contains only the signal sequence (SS) and the extracellular N-terminal domain. The truncated gE protein (gE truncated) contains the signal sequence, extracellular N-terminal domain, transmembrane (TM) domain and part of the C-terminal domain with one point mutation in the trans-Golgi network (TGN) localization motif, wherein AYRV sequence was modified to AARV (Y569A). The full-length gE protein (gE full-length) contains the entire wild-type open reading frame of the glycoprotein. B Western blot of cell lysates (left) and cell supernatants (right) after transfection with the indicated gE-expressing mRNA constructs. gE-FL gE full-length, gE-T gE truncated, and gE-SgE soluble protein. Red bands correspond to the gE protein, green bands correspond to beta actin that is used as loading control. The observed molecular weight sizes for gE-FL (90kDa) and gE-T (80kDa) correspond to their partially glycosylated forms. gE-S (observed at 75kDa) is not detected in the cell lysates, as expected, but is instead detected in the supernatant (right). C, D Detection of gE expression on cell surface (gE full-length and gE truncated) and in supernatant (gE soluble) by ELISA. EC50 values (in nM) are shown as MeanSD; R square values are shown to highlight the goodness of fit. The detection is performed using anti-gE antibodies. E, F Binding of human Fc fragment to cell surfaces expressed gE (gE full-length and gE truncated) (E) and gE in supernatant (F) to demonstrate the appropriate conformation and functional nature of the gE proteins. EC50 values (in nM) are shown as MeanSD; R square value is shown to highlight the goodness of fit.

After generation of the mRNA constructs, we successfully demonstrated the expression of all three gE variants in transfected HEK293FT cells by Western blotting (Fig. 1B) and in transfected HeLa cells by in-cell ELISA (for gE full-length and gE truncated; Fig. 1C) and supernatant ELISA (for gE soluble; Fig. 1D). The various gE proteins migrated on the PAGE gel at expected molecular weights with a clear difference between the sizes of the full length and truncated (gE truncated and gE soluble) versions of the protein. As expected, the soluble gE was not detected in cell lysates but was detected in the supernatants of transfected cells both by Western blot (Fig. 1B) and by ELISA (Fig. 1D). In-cell ELISA (gE full-length and gE truncated) and ELISA (gE soluble) showed that the expression levels of full-length gE and truncated gE antigens (Fig. 1C) were similar to the soluble gE antigen (Fig. 1D). This was further confirmed when HEK293FT cells, expressing the three gE antigen variants, were treated with Brefeldin A and we observed similar expression levels via Western blot (data not shown). Additionally, we characterized the functionality of the expressed gE proteins by their ability to bind human Fc. To that end, we developed Fc-binding ELISAs and observed that all three gE variants bound the recombinant human Fc similarly (Fig. 1E for gE full-length and gE truncated antigens binding to Fc; Fig. 1F for gE soluble antigen binding to Fc). These results confirmed the successful designs of the mRNA constructs encoding the three gE antigen variants, their appropriate expression upon transfection, and demonstration of functional antigenic conformation via human Fc-binding.

To generate vaccine candidate materials for the in vivo studies, the three gE-encoding (gE full length, gE truncated and gE soluble protein) mRNAs were produced by in vitro transcription, purified using lithium chloride precipitation, and stored at 65C until further use. The purified mRNAs were tested for the following key attributes: concentration, identity, purity/integrity, poly(A) tail length, % capping efficiency, % N1-methyl-pseudouridine (m1) incorporation, and levels of various impurities (e.g., RNase, endotoxin, E.coli DNA and residual NTPs). These analytical test results are shown in Supplementary Table S2. Thereafter, all three purified gE-encoding mRNAs were encapsulated in either NOF-lipid-based LNPs or SM102-lipid-based LNPs and the final formulated mRNA-LNPs were tested for the following critical attributes: Particle size, Polydispersity index (PDI), % mRNA encapsulation, % mRNA purity post encapsulation and mRNA concentration. The analytical test results of the six mRNA-LNPs are shown in Supplementary Table S3.

We aimed to evaluate immunogenicity of the three gE-encoding GLB mRNA-LNP vaccine candidates in mice. However, before evaluating all three gE variants, we wanted to conduct a preliminary study using the mRNA-LNP formulation encoding the full-length glycoprotein E (gE). The LNP formulation was based on proprietary cationic lipids from NOF corporation. The aim of this preliminary study was to quickly test if the novel NOF-LNP formulation was effective in delivering the mRNA in vivo, using the gE full-length antigen, before conducting the full comparative evaluation of the gE variants. As positive control, the currently approved subunit vaccine Shingrix was used.

To mimic pre-existing immunity against VZV, which is expected to be present in dormant state in the target human population, C57BL/6 female mice were primed with a full human dose (500L) of the live-attenuated Varicella Zoster virus (Varivax) by subcutaneous administration. It should be noted that the live-attenuated VZV (Varivax) cannot replicate in mouse cells and establish latency in this animal. Mice were immunized with two intramuscular injections of the gE full-length encoding mRNA-LNP (NOF) candidate, 4- and 8-weeks post Varivax priming, as shown in Fig. 2A. Immunizations were performed at a dose of 5g per animal, in a total volume of 50L per mouse (25L in each hind limb). Mice injected with Varivax only or saline were included as controls.

Female C57BL/6 mice were primed with a full human dose of the live attenuated VZV vaccine (Varivax) by subcutaneous administration. Mice were then injected intramuscularly with 5g of mRNA-LNP vaccine candidates, expressing VZV gE full-length, or saline (Varivax only group) at weeks 4- and 8- post Varivax administration. NOF-LNP formulated mRNA, delivering gE full-length, is the test candidate while Shingrix is used as a positive control. A Scheme of immunizations and sample collections schedule. B End-point titers of gE-specific IgG binding antibodies detected in mice at the indicated timepoints and evaluated by ELISA. Arrows indicate the two mRNA-LNP/Shingrix immunization timepoints. Data shown as MeanSEM, and is representative of two independent experiments using 10 animals per group. Y-axis represents Log10 end-point titers; X-axis represents weeks post-Varivax prime. C Antigen-specific effector T cell responses measured from whole blood using a murine IFN-/IL-2 Double-Color Enzymatic ELISpot Assay. Data shown as MeanSEM. Y-axis represents Spot Forming Cells (SFCs) per million peripheral blood cells. Each SFC corresponds to an effector T cell secreting either one or both cytokines in response to stimulation by the gE overlapping peptides pool.

Anti-gE IgG binding antibodies were detected by ELISA from serum samples collected at 0-, 4-, 6-, 8-, and 10-weeks post Varivax prime. Immunization of mice with 5g of gE full-length mRNA-LNP (NOF) induced high levels of anti-gE serum IgG binding antibodies that were comparable to those elicited by Shingrix, as shown in Fig. 2B. Anti-gE binding antibody titers observed in animals immunized with mRNA-LNP (NOF) vaccine increased significantly after each immunization, when compared to animals primed with Varivax only.

Effector T cell responses were assessed from peripheral blood 2 weeks post Varivax prime (baseline response), and 1 week post the first and second mRNA-LNP immunizations using the murine IFN-/IL-2 Double-Color Enzymatic ELISpot Assay. gE-specific activated T cells secreting either IFN- or IL-2 or both cytokines, after re-stimulation with gE overlapping peptides, were quantified (Fig. 2C). At baseline, the number of spot-forming cells (SFC) in all groups were similarly low, below 10 SFC per million blood cells. However, following two immunizations with 5g of mRNA-LNP (NOF) vaccine candidate, all animals developed strong gE-specific effector T cell responses that were higher than those observed in mice administered with two injections of Shingrix. No long-lasting T-cell response was detected in animals primed with Varivax alone. Taken together, the data from this preliminary study shows that the GLB mRNA-LNP (NOF) formulation is successful in delivering the gE glycoprotein and successful in eliciting a strong immunogenic response, comparable to Shingrix, in mice.

Based on the success of the above preliminary in vivo study in mice, we designed this expanded comparative immunogenicity study to evaluate all three mRNA-LNP vaccines candidates, encoding the three different versions of the gE antigen, and to compare them to Shingrix. For this study, the three gE antigen variants-encoding mRNAs were formulated in two different LNP formulations for in vivo testing: one using the proprietary NOF LNP and the other using SM102 LNP, as a LNP comparator. SM102 LNP was chosen as a comparator because successful delivery of mRNA encoding for VZVs gE by SM102 LNP has been reported earlier by Monslow et al.27. Each mRNA-LNP candidate was produced, tested for critical attributes (mRNA content, mRNA integrity and purity, LNP size and polydispersity) and thereafter frozen at <65C until use in the study. In this study, two different antigen doses for each of the gE antigens were tested: a high dose of 5g and a low dose of 1g.

Consistent with the previous mouse study (Fig. 2A), this study in C57BL/6 female mice was also similarly designed. All mice received a full human dose (500L) of the live attenuated Varicella vaccine (Varivax) by subcutaneous administration to set the initial VZV infection. 4 weeks post Varivax priming, mice were administered with two intramuscular injections of the formulated mRNA, 4 weeks apart (Fig. 3A). Additionally, one group of mice was administered with 5g of Shingrix (1/10 of the human dose) twice, 4 weeks apart, as positive control or an active comparator. Vaccines were administered in a total volume of 50L per mouse (25L in each hind limb). Mice injected with Varivax only and saline were included as (negative) controls.

Female C57BL/6 mice (5 animals per group) were primed with a full human dose of the live-attenuated VZV) vaccine (Varivax) by subcutaneous administration. Mice were then injected intramuscularly with 1 or 5g of mRNA-LNP vaccine candidates, encoding the three gE variants, or saline (Varivax only group) at 4 and 8 weeks post Varivax administration. A Scheme of immunization and sample collection schedule. B Longitudinal Log10 end-point titers (Y-axis) of gE-specific IgG binding antibodies detected in sera collected from mice at the indicated timepoints and evaluated by ELISA. Arrows indicate mRNA-LNP/Shingrix immunization time points. Data shown as MeanSEM. C Quantitative assessment of anti-gE serum IgG binding antibodies in mice from all vaccinated groups at 12 weeks post Varivax prime, assessed by ELISA and expressed as area under the curve (AUC) (Y-axis) based on absorbance values. Data shown as MeanSEM.

Anti-gE binding antibodies were detected by ELISA from sera of mice collected on 0, 4, 8, 12, 16, 20, and 24 weeks. Serum IgG binding antibody levels induced by NOF LNPs encapsulating 5g of mRNA were equivalent to antibody levels observed in animals vaccinated with Shingrix (Fig. 3B). Moreover, NOF LNP-formulated vaccine induced higher levels of gE-specific binding antibodies when compared to SM102 LNP-formulated vaccines in a dose-dependent manner (Fig. 3C). The peak binding antibody response was observed at week 12 i.e., 4 weeks post 2nd vaccination (Fig. 3B, C). As expected, mice vaccinated with saline had no detectable anti-gE serum IgG throughout the study.

Previous studies suggest that CD4+ T cells play a critical role in protecting against reactivation of VZV28,29. The decline in VZV-specific CD4+ T-cell responses has been associated with an increased risk of herpes zoster in older adults30,31. Moreover, immunocompromised individuals with impaired CD4+ T-cell function, such as people living with HIV, but not antibody deficiencies, are at a higher risk of developing herpes zoster and are more likely to experience severe and prolonged episodes28. Therefore, vaccines that can boost CD4+ T cell responses are believed to provide additional protection against reactivation of VZV. To that end, to assess amplitude and kinetics of T cell responses induced by the various mRNA-LNP vaccines encoding the three gE antigen variants, peripheral blood was collected 2 weeks post Varivax prime, and at 1 and 2 weeks post each vaccination (mRNA-LNP or Shingrix), as depicted in Fig. 3A. Peripheral blood mononuclear cells were stimulated with a gE overlapping peptide pool, and the number of gE-specific cells secreting IFN- and/or IL-2 was quantified by dual-color ELISpot. Priming with Varivax induced very weak T-cell responses in mice (Fig. 4A), as also previously described by others19,27. Effector T cell responses peaked at day 7 post each vaccination, either by the mRNA-LNP vaccines or the active control (Shingrix). Overall, the mRNA-LNP vaccine expressing the soluble version of gE performed poorly when compared to mRNA-LNP vaccines encoding the full-length gE or the truncated gE; regardless of the type of LNP (NOF vs. SM102) formulation used (Fig. 4A, B). Remarkably, the three NOF LNP-formulated vaccines encoding each of the three gE antigen variants, induced very high levels of poly-functional effector T cells, evidenced by secretion of more than one cytokine simultaneously, which were higher than levels induced by the Shingrix vaccinated animals.

A, B Female C57BL/6 mice (5 animals per group) were primed with a full human dose of the live attenuated VZV vaccine (Varivax) by subcutaneous administration. Mice were injected intramuscularly 5g of the mRNA-LNP vaccine candidates, expressing the three gE variants, or Shingrix at 4 and 8 weeks post Varivax administration. A, B Antigen-specific effector T cell responses were measured from whole blood cells collected at week 5 i.e., 1 week post 1st immunization (A) or week 9, i.e., 1 week post 2nd immunization (Busing a murine IFN-/IL-2 Double-Color Enzymatic ELISpot Assay. Data shown as MeanSEM. Y-axis in both panels, A and B, represents Spot Forming Cells (SFCs) per million peripheral blood cells. Each SFC corresponds to an effector T cell secreting either one or both cytokines in response to the gE overlapping peptides pool.

To bolster the above findings, we conducted an additional study to measure effector T cell responses from splenocytes, collected 1 week post 2nd immunization with mRNA-LNP (NOF), mRNA-LNP (SM102) or Shingrix, by intracellular cytokine staining (ICS). In this study, mice were administered with two intramuscular injections of the LNP (NOF or SM102) formulated mRNA or Shingrix, 4 weeks apart, without Varivax priming (Fig. 5A). Mice injected with saline were included as (negative) controls. Splenocytes obtained a week after the second immunization were stimulated with gE overlapping peptide pool, and the number of gE-specific CD4+ or CD8+ T cells secreting IFN-, TNF- and/or IL-2 were quantified by flow cytometry (Supplementary Figure S1). The gE-specific effector T cell responses were predominantly CD4+ T cell-mediated, since less than 0.5% of the CD8+ T cells in the spleen detected were secreting cytokines upon stimulation with gE peptides (Fig. 5B and Supplementary Figure S2A). Administration of NOF or SM102 formulated mRNA-LNP vaccine candidates induced potent CD4+ T cell responses, as seen by the number of gE-specific CD4+ T cells secreting either one, two or all three of the cytokines IFN-, TNF- and IL-2 (Fig. 5C and Supplementary Figure S2B). Importantly, both NOF and SM102-formulated mRNA-LNP vaccines induced higher levels of CD4+ T cell responses than Shingrix.

A Animals were divided in groups of 7, and subsequently immunized with 2 intramuscular doses, 4 weeks apart, of gE mRNA-LNP (NOF or SM102) or Shingrix. Mice injected with saline were included as negative controls. One week after the last immunization, spleens were harvested and stimulated with overlapping peptide pools from VZV gE protein, and percentage of CD8+ (B) and CD4+ (C) T cells producing IFN-, TNF-, and IL-2, was measured by flow cytometry.

Effective vaccines are expected to generate adaptive immunological memory in the B cell (BMEM) and T cell (TMEM) memory compartments. This memory is crucial for rapid recall of the immune responses to avoid re-activation of VZV and causation of herpes Zoster disease27,32. To assess if vaccination with the gE antigen encoding mRNA-LNP vaccine candidates could lead to long-term persistence of humoral responses, the presence of gE-specific long-lived plasma cells was investigated in the bone marrows and effector memory CD4+ T cells in the spleens of mice, collected 16 weeks post 2nd immunization, as depicted in schematics on Fig. 3A. gE-specific long-lived plasma cells (LLPCs), quantified as the number of bone marrow-derived anti-gE antibody (IgG) secreting cells (ASC) by B cell ELISpot assay, induced by 5g of mRNA formulated with NOF LNP, were comparable to responses observed in animals vaccinated with Shingrix (Fig. 6A). Additionally, gE-specific CD4+ effector memory T cells, characterized as CD4+ CD44+ CD62L-, were quantified from spleens. We observed that gE-specific effector memory CD4+ T cell responses, induced by 5g of mRNA formulated with NOF LNP, were comparable to responses observed in animals vaccinated with Shingrix (Fig. 6B). Cumulatively, based on the overall gE-specific antibody titers, antigen-specific T cell responses and LLPCs and T cell memory results, we selected the gE full-length for future studies to support clinical development of this vaccine candidate.

C57Bl/6 mice (5 animals per group) were primed with live attenuated VZV vaccine (Varivax), and vaccinated twice, 4 weeks apart, with the mRNA-LNP vaccine candidates or Shingrix. Immunological memory was evaluated 16 weeks post last immunization. A Long lived plasma cells in the bone marrow secreting antibodies that bind to VZV gE, quantified by B cell ELISpot assay. Y-axis represents Spot Forming Cells (SFCs) per million bone marrow-derived cells. B Percentages of effector memory CD4+CD44+CD62L- T cells (Y-axis) secreting either IFN-, TNF-, and IL-2 alone or any of the two or all three cytokines. Data shown as MeanSEM.

Despite the high efficacy of Shingrix, vaccinees have reported severe local and systemic reactions post vaccination21,22. Thus, aware of the pronounced reactogenicity of Shingrix, one of our major goals was to develop a mRNA-LNP vaccine against herpes zoster that is at least comparable with respect to immunogenicity of Shingrix but with potentially lower induction of systemic inflammation.

To assess systemic inflammation induced by the selected gE full-length mRNA-LNP vaccine candidates, pro-inflammatory cytokines were measured from sera collected before immunization and 6h and 24h after the 1st immunization with mRNA-LNP (NOF) formulated vaccine candidate or mRNA-LNP (SM102) formulated vaccine candidate or Shingrix, using the LEGENDplex Mouse Anti-Virus Response Panel. Interestingly, both NOF and SM102 lipid-formulated mRNA-LNP vaccines induced significatively lower levels of pro-inflammatory cytokines such as MCP-1 (Fig. 7A), CXCL-1 (Fig. 7B), and CXCL-10 (Fig. 7C) post vaccination than Shingrix. Other pro-inflammatory cytokines such as interferons, IL-1 and IL-6 (that were included in the LEGENDplex Mouse Anti-Virus Response Panel) were not detected at any of the time points across all groups. These findings suggest that additional investigations will be necessary in future to allow for the full assessment of local and systemic toxicity of our mRNA-LNP in comparison to Shingrix.

Female C57BL/6 mice (7 animals per group) were immunized with 5g of either SM102 LNP-formulated mRNA encoding gE full-length or NOF LNP-formulated mRNA encoding gE full-length or Shingrix or saline alone (negative control). Pro-inflammatory cytokines (MCP-1 in panel A, CXCL1/KC in panel B, and CXCL10/IP-10 in panel C) were quantified in serum of immunized animals pre-dose, 6h and 24h post dosing, using LEGENDplex Mouse Anti-Virus Response flow-based multiplexed assay. Y-axis denotes the cytokine concentrations in pg/mL. Data shown as MeanSEM. Two-way Analysis of Variance (ANOVA) with Tukeys multiple comparison test was performed to determine statistical significance. *p<0.05, **p<0.005, ***p<0.0005, ****p<0.0001; ns - not significant. MCP-1 monocyte chemoattractant protein-1, CXCL1/KC chemokine (C-X-C motif) ligand 1/keratinocyte-derived chemokine, CXCL10/IP-10 chemokine (C-X-C motif) ligand 10/ IFN--inducible protein 10.

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Potent and long-lasting humoral and cellular immunity against varicella zoster virus induced by mRNA-LNP vaccine ... - Nature.com

Experts in Industry Wrangle Over Whether Combo Vaccines Are Beneficial for Adults – Medpage Today

April 6, 2024

WASHINGTON -- The benefits of combination vaccines may seem obvious (fewer visits, less discomfort), but their development for adults is not without challenges, pharmaceutical company experts said at the World Vaccine Congress on Wednesday.

Combination vaccines have been available for children for decades, but whether they're also needed for adults, and for which viruses, have been debated.

"I think combination vaccines have the potential for enormous public health benefit," said Kayvon Modjarrad, MD, PhD, executive director of vaccine research and development for Pfizer.

In addition to the convenience of fewer shots and fewer sore arms, combination vaccines have the potential to reduce the burden of vaccination on the overall healthcare system and improve equity, he noted.

Francesca Ceddia, MD, chief medical affairs officer for Moderna, said another perk of combined vaccines is the potential to increase coverage rates.

Despite rates of hospitalizations and deaths from COVID-19 being two to five times higher than those for influenza, people don't question flu vaccines the way they do COVID vaccines, Ceddia said, adding that she anticipates that a combination COVID/flu vaccine could help normalize COVID vaccination.

"People do not question why [they] should get diphtheria, tetanus, pertussis, etc.," she pointed out.

Ceddia also highlighted the potential to increase vaccine uptake for lesser known illnesses -- for example, by pairing vaccination for respiratory syncytial virus (RSV) with human metapneumovirus (HMPV).

The primary criteria for pairing two diseases in one vaccine is to have overlapping epidemiology and indications, the panelists said.

In the case of RSV and HMPV, both are respiratory pathogens that affect the upper and lower respiratory tracts, and both impact a similar population -- young children and older adults, Ceddia told MedPage Today in a follow-up email, adding that HMPV is "very similar" to the antigen for RSV.

The viruses also have matching seasonality and a similarly underestimated burden of disease, even more so for HMPV, she said. Moderna is working on such a vaccine and to date has completed phase I trials in pediatric populations.

Looking at less ideal combinations, duration of protection matters. It's unclear how long the current RSV vaccine will protect people, but if that duration is longer than for COVID or flu, pairing RSV with either gets increasingly more complicated. "This is what we're learning," Ceddia said, based on data that are currently being collected.

Piyali Mukherjee, MPH, vice president and head of global medical affairs, vaccines, for GSK, also noted that she sees clear benefits from combination vaccines in adults, and "with so many new technologies -- mRNA, mAbs [monoclonal antibodies] -- I'm sure this space will only grow."

Robert Walker, MD, chief medical officer for Novavax, was more skeptical.

In considering the "value proposition" of combination vaccines for adults, one should look at the injection burden and current vaccine schedule, he said. Children receive approximately 27 separate injections in their first 2 years, with as many as six in one visit.

"Clearly, there's an injection burden there, and there's a medical need," he said. "Do we have the same problem in the adult sector?"

Walker also challenged the idea that a combination flu/COVID vaccine might improve COVID vaccination uptake.

"Equally possible is that the COVID [vaccine] could be pulling the flu acceptance down," he said.

However, a 2023 meta-analysis suggested the opposite: that combining flu vaccines and COVID boosters "can be an effective strategy for increasing the uptake of the latter by populations that have shown reluctance against taking it," the authors wrote.

Ceddia is confident that the negativity and misconceptions around COVID vaccines will dissipate, she told MedPage Today, especially as awareness that vaccination prevents not only acute symptoms but also long COVID increases.

Furthermore, reducing the number of visits for vaccine administration "saves cost and time," she added. "If we assume [combination vaccines] could potentially increase compliance and adherence to vaccination, and improve coverage rates, there would be savings in terms of healthcare cost utilization."

Panelists were also asked about other specific challenges in development, including the potential for immune interference -- the belief that the immune system can become overloaded with simultaneous exposures to more than one vaccine -- and the "upper limit of toxicity" (the point at which increasing the dose of a vaccine changes the adverse event profile).

Modjarrad stressed that these are important considerations. There are already inherent complexities to developing a combination COVID/flu vaccine. For instance, there are multiple antigens present in the flu vaccine itself, which is why Pfizer is taking a "very deliberate, phased approach to this," and starting with two vaccines, not four or five, he said.

Mukherjee added that some immune interference is to be expected. That's why it's important to know what level of interference actually matters, then do studies and collect the data, she said.

As for vaccine reactogenicity, "this is where platform optimization will become very, very important," she noted. In early studies of GSK's partnership with CureVac, for example, "even at the highest dose ranges [that were tested], you do have a much lower level of reactogenicity."

Walker said that Novavax has seen interference between flu and COVID in phase II studies using recombinant protein nanoparticle platform technology, and therefore increased the amount of antigen, but the platform "can accommodate a lot of antigen."

"As we drive up antigen, our experience has been that the reactogenicity is indistinguishable from the lowest antigen dose levels," he said.

Also, as Ceddia pointed out, regulators are quick to remind companies that if a vaccine doesn't perform in the same way as the original, it's unlikely to move forward.

"It's a very complex field," she said, but knowing what has worked in the pediatric space, "there is reason to believe that it could also work in the adult space."

Shannon Firth has been reporting on health policy as MedPage Today's Washington correspondent since 2014. She is also a member of the site's Enterprise & Investigative Reporting team. Follow

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Experts in Industry Wrangle Over Whether Combo Vaccines Are Beneficial for Adults - Medpage Today

REPORT: Army and Air Force were slow to act on COVID-19 vaccine religious exemption requests – 13newsnow.com WVEC

April 6, 2024

More than 16,000 troops sought waivers. Just 339 were granted.

NORFOLK, Va. There are new questions about how the military handled thousands of cases where service members refused the COVID-19 vaccine because of "sincerely held religious beliefs."

A Marchreport from the Defense Department Inspector Generalfound that while the military branches largely followed policy when considering waivers for service members who sought religious exemptions from having to take the COVID-19 vaccine, the Army and Air Force did not meet the DOD time guidelines in processing those requests.

The Army has a 90-day deadline for processing requests but, the cases averaged 192 days to receive a decision.

In the Air Force, requests averaged 168 days to adjudicate, despite the deadline being 30 days.

Concerns raised by impacted service members prompted multiple lawsuits alleging that the DOD and service branches were blanketly denying religious waiver requests.

"That demonstrates outright religious hostility. That is afford to the Constitution and federal law." First Liberty Institute attorney Mike Berry told 13 News Now in January 2022.

Overall, the numbers are eye-opening. Of more than 16,000 religious exemption requests received, just 339 were approved. 13,387 were denied.

According toDefense Department statistics, more than 2 million military members did get their COVID shots.

But, according to the Associated Press over 8,400 troops were discharged due to non-compliance.

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REPORT: Army and Air Force were slow to act on COVID-19 vaccine religious exemption requests - 13newsnow.com WVEC

What is the killed measles vaccine and what does it mean if you got one – WGN TV Chicago

April 6, 2024

Last month, the Centers for Disease Control and Prevention issued awarningover the increase in measles outbreaks. And this week, the Chicago Department of Public Health warned about possible measles exposure at several city locations.

While measles is most dangerous for young children and pregnant women, the CDC warns everyone especially those planning international travel of any kind should get vaccinated to prevent the virus spread.

As far as who does not need the MMR Vaccine, the CDC lists the following criteria:

Additionally, the CDC says, if you received a measles vaccine in the 1960s, you may not need to be revaccinated.

Those who received the vaccine in the 1960s should check their vaccine records. If you received the LIVE measles vaccine in the 1960s, the CDC says you do not need to be revaccinated.

The killed measles vaccine is an earlier formulation of measles vaccine that is no longer used. The CDC says if your vaccine documentation indicates you received the killed measles vaccine, you should talk with you healthcare provider about getting revaccinated with the current MMR vaccine.

The CDC says this recommendation is intended to protect those who may have received killed measles vaccine, which was available in 1963-1967 and was not effective.

Additionally, according to the CDC, being before 1957 provides only presumptive evidence for measles, mumps, and rubella. Before vaccines were available, nearly everyone was infected with measles, mumps, and rubella viruses during childhood. The majority of people born before 1957 are likely to have been infected naturally and therefore are presumed to be protected against measles, mumps, and rubella. Healthcare personnel born before 1957 without laboratory evidence of immunity or disease should consider getting two doses of MMR vaccine.

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What is the killed measles vaccine and what does it mean if you got one - WGN TV Chicago

Mother appeals case of teen’s forced COVID shot to state Supreme Court – Carolina Journal

April 6, 2024

A Guilford County mother hopes the state Supreme Court will take the case of her teenage sons forced COVID vaccine shot. The mother and son sued the Guilford County school board and the Old North State Medical Society over the 2021 incident.

A unanimous state Court of Appeals panel ruled in March against mother Emily Happel and son Tanner Smith. Appellate judges agreed that the federal Public Readiness and Emergency Preparedness Act of 2005 protected the school board and medical society against legal action.

Happel and Smith filed a petition Friday asking the states highest court to reverse that ruling.

The pandemic that occurred from 2020-2022 caused a seismic shift in the social, medical, political, and legal landscape of not only the State of North Carolina, not only the United States, but the world as a whole, wrote lawyer David Steven Walker. How the government chose to deal with the pandemic, especially concerning the administration of vaccines that had been granted emergency use authorizations, was and is a hotly contested issue, one that is certainly of significant public interest.

This public interest is even more significant when the issue revolves around the vaccination of a minor and the allegation that neither the minor nor the minors parent consented to the administration of the vaccine, Walker added.

The case deals with the interplay between duty of the courts of North Carolina to remedy constitutional and other legal violations and a federal law that defendants purport forecloses that opportunity, Walker wrote.

The trial court and the Court of Appeals interpreted the PREP Act so broadly as to shield nearly every act, no matter how egregious, from any legal consequence, according to the petition. Further, the Court of Appeals and the trial courts decision rendered totally useless N.C. Gen. Stat. 90-21.5(a1) which prohibited the very acts committed by defendants. It is now a law of aspiration, with no consequence for its blatant violation.

The quoted state law NCGS 90-21.5(a1) says, Notwithstanding any other provision of law to the contrary, a health care provider shall obtain written consent from a parent or legal guardian prior to administering any vaccine that has been granted emergency use authorization and is not yet fully approved by the United States Food and Drug Administration to an individual under 18 years of age.

The Appeals Court issued a unanimous March 5 decision against the mother and son despite labeling the forced vaccination egregious.

Plaintiffs argue the trial court erred in determining that the PREP Act is applicable to this case and provides immunity to both Defendants, Judge April Wood wrote. Due to the sweeping breadth of the federal liability immunity provision in the PREP Act, we are constrained to disagree.

Bound by the broad scope of immunity provided by the PREP Act, we are constrained to hold it shields Defendants, under the facts of this case, from Plaintiffs claims relating to the administration of the COVID-19 vaccine, Wood added.

In August 2021, Smith was a 14-year-old Western Guilford High School football player. His family learned in a letter from the Guilford schools that Smith might have been affected by a COVID-19 cluster involving the team. He would not be allowed to return to practice until getting a COVID test.

Free testing would be provided at Northwest Guilford High School. The letter indicated ONS Medical Society would conduct the testing and consent for testing is required, Wood wrote.

Smiths stepfather drove him to the testing site and waited outside the building. The teenager was asked to fill out a form while a clinic worker tried unsuccessfully to contact his mother. Smith and his family didnt know the clinic also provided COVID-19 vaccine shots.

After failing to make contact with Tanners mother, one of the workers instructed the other worker to give it to him anyway. Tanner stated he did not want a vaccine and was only expecting a test, but one of the workers administered a Pfizer COVID-19 vaccine to him, Wood wrote.

Happel and Smith filed suit in August 2022. A trial judge dismissed the case in March 2023.

Appellate judges ruled that both the school board and medical society were covered by the federal PREP Act. A declaration from the secretary of the US Department of Health and Human Services in March 2020 offered protection related to the COVID-19 vaccine.

[W]e hold ONS Medical Society is a covered person as a program planner that administered a vaccine clinic, and individually administered vaccines to individuals. The declaration clearly provides that a program planner may be a private sector employer or community group when it carries out the described activities including administration of a covered countermeasure, Wood wrote.

The same law also applied to the Guilford school board. We are convinced by the Secretarys interpretation in the declaration that a covered person under the PREP Act includes a state or local government . . . [that] provides a facility to administer or use a Covered Countermeasure. We hold this language includes the Board, which provided a facility Northwest Guilford High School for the administration of the COVID-19 vaccines, Wood wrote.

Wisely or not, the plain language of the PREP Act includes claims of battery and violations of state constitutional rights within the scope of its immunity, and it therefore shields Defendants from liability for Plaintiffs claims, Wood added.

The Appeals Court noted that North Carolinas General Assembly amended state law in 2021 to require parental consent before a vaccine granted emergency use authorization may be administered to a minor.

Its intent is to prevent the egregious conduct alleged in the case before us, and to safeguard the constitutional rights at issue Emilys parental right to the care and control of her child, and Tanners right to individual liberty, Wood wrote. Notwithstanding, the statute remains explicitly subject to any other provision of law to the contrary under the broad provision preempting state law in the PREP Act.

The PREP Act provides only one exception for a Federal cause of action against a covered person for death or serious physical injury proximately caused by willful misconduct. Because Plaintiffs have not made any such allegations in their complaint, we are constrained to conclude the PREP Act preempts the protections provided by state law, Wood wrote.

Judges Allegra Collins and Jeff Carpenter joined Woods decision.

Originally posted here:

Mother appeals case of teen's forced COVID shot to state Supreme Court - Carolina Journal

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