Cryptic vaccine-associated adverse events: The critical need for a new vaccine safety surveillance paradigm to improve public trust in vaccines.

Vaccination is one of the most important public health tools in the prevention of infectious diseases, and in preserving life and health. While vaccines are generally safe and usually produce only transient side effects, other types of vaccine-associated adverse events do occur. Some of these reactions are immediate and easily observable or measurable, such as swelling at the injection site or a transient fever. Others however are not immediately obvious, or are even clinically "silent" or cryptic, making them challenging to identify and link directly to a vaccine. It is critical to be vigilant about rare, silent, or subtle reactions. Public health agencies and healthcare providers can play a much more favorable and vital role in establishing vaccine trust by enlarging the current vaccine safety paradigm, and in publishing and communicating, in full, these risks and benefits transparently to the public. While there are challenges in collecting and studying cryptic adverse events characterized by subjective symptoms without biomarkers, rigorous pharmacovigilance, continued research, and high-quality study designs can assist in better understanding and addressing these concerns - and in building public trust about vaccines and vaccine safety surveillance completeness.

Immunogenicity of a peptide-based vaccine for measles: a pilot evaluation in a mouse model.

Although neutralizing antibody is an established correlate of protection for measles, T cell-mediated responses play at least two critical roles in immunity to measles: first, through provision of 'help' enabling robust humoral immune responses; and second, through clearance of measles virus-infected cells. Previously, we identified 13 measles-derived peptides that bound to human leukocyte antigen (HLA) molecules in Priess cells infected with measles virus. In this study, we evaluated the immunogenicity of these peptides in a transgenic mouse model. Our results demonstrated that these peptides induced Th1-biased immune responses at varying levels. Of the 13 peptides, the top four immunogenic peptides were further selected for a viral challenge study in mice. A vaccine based on a combination of these four peptides reduced morbidity and weight loss after viral challenge compared to placebo. Our results emphasize the potential of T cell-mediated, peptide-based vaccines against measles.

Restricted Omicron-specific cross-variant memory B-cell immunity after a 3rd dose/booster of monovalent Wuhan-Hu-1-containing COVID-19 mRNA vaccine.

The responsiveness/cross-binding of vaccine-induced memory B cells/MBCs to previous and emerging divergent SARS-CoV-2 variants (e.g., Omicron) is understudied. In this longitudinal study subjects receiving two or three doses of monovalent ancestral strain-containing COVID-19 mRNA vaccine were evaluated. In contrast to others, we observed significantly lower frequencies of MBCs reactive to the receptor-binding domain/RBD, the N-terminal domain/NTD, and the S1 of Omicron/BA.1, compared to Wuhan and Delta, even after a 3rd vaccine dose/booster. Our study is a proof of concept that MBC cross-reactivity to variants with greater sequence divergence from the vaccine strain may be overestimated and suggests that these variants may exhibit immune escape with reduced recognition by circulating pre-existing MBCs upon infection.

Early B cell transcriptomic markers of measles-specific humoral immunity following a 3rd dose of MMR vaccine.

B cell transcriptomic signatures hold promise for the early prediction of vaccine-induced humoral immunity and vaccine protective efficacy. We performed a longitudinal study in 232 healthy adult participants before/after a 3rd dose of MMR (MMR3) vaccine. We assessed baseline and early transcriptional patterns in purified B cells and their association with measles-specific humoral immunity after MMR vaccination using two analytical methods ("per gene" linear models and joint analysis). Our study identified distinct early transcriptional signatures/genes following MMR3 that were associated with measles-specific neutralizing antibody titer and/or binding antibody titer. The most significant genes included: the interleukin 20 receptor subunit beta/IL20RB gene (a subunit receptor for IL-24, a cytokine involved in the germinal center B cell maturation/response); the phorbol-12-myristate-13-acetate-induced protein 1/PMAIP1, the brain expressed X-linked 2/BEX2 gene and the B cell Fas apoptotic inhibitory molecule/FAIM, involved in the selection of high-affinity B cell clones and apoptosis/regulation of apoptosis; as well as IL16 (encoding the B lymphocyte-derived IL-16 ligand of CD4), involved in the crosstalk between B cells, dendritic cells and helper T cells. Significantly enriched pathways included B cell signaling, apoptosis/regulation of apoptosis, metabolic pathways, cell cycle-related pathways, and pathways associated with viral infections, among others. In conclusion, our study identified genes/pathways linked to antigen-induced B cell proliferation, differentiation, apoptosis, and clonal selection, that are associated with, and impact measles virus-specific humoral immunity after MMR vaccination.

A multifaceted approach for identification, validation, and immunogenicity of naturally processed and in silico-predicted highly conserved SARS-CoV-2 peptides.

SARS-CoV-2 remains a major global public health concern. Antibody waning and immune escape variant emergence necessitate the development of next generation vaccines that induce cross-reactive durable immune responses. T cell responses to SARS-CoV-2 demonstrate higher conservation, antigenic breadth, and longevity than antibody responses. Therefore, we sought to identify pathogen-derived T cell epitopes for a potential peptide-based vaccine. We pursued an approach leveraging: 1) liquid chromatography and tandem mass spectrometry (LC-MS/MS)-based identification of peptides from ancestral SARS-CoV-2-infected cell lines, 2) epitope prediction algorithms, and 3) overlapping peptide libraries. From this strategy, we identified 380 unique SARS-CoV-2-derived peptide sequences, including 53 antigenic HLA class I and class II peptides from multiple structural and non-structural/accessory viral proteins. These peptide sequences were highly conserved across variants of concern/interest (VoC/VoIs), and are estimated to achieve coverage of >96% of the world population. Our findings validate this discovery pipeline for peptide identification and immunogenicity testing, and are a crucial step toward the development of a next-generation multi-epitope SARS-CoV-2 peptide vaccine, and a novel vaccine platform methodology.

Polygenic Prediction of Cellular Immune Responses to Mumps Vaccine.

In this report, we provide a follow-up analysis of a previously published genome-wide association study of host genetic variants associated with inter-individual variations in cellular immune responses to mumps vaccine. Here we report the results of a polygenic score (PGS) analysis showing how common variants can predict mumps vaccine response. We found higher PGS for IFNγ, IL-2, and TNFα were predictive of higher post-vaccine IFNγ (p-value = 2e-6), IL-2 (p = 2e-7), and TNFα (p = 0.004) levels, respectively. Control of immune responses after vaccination is complex and polygenic in nature. Our results suggest that the PGS-based approach enables better capture of the combined genetic effects that contribute to mumps vaccine-induced immunity, potentially offering a more comprehensive understanding than traditional single-variant GWAS. This approach will likely have broad utility in studying genetic control of immune responses to other vaccines and to infectious diseases.

Excessive daytime sleepiness is associated with impaired antibody response to influenza vaccination in older male adults.

Background: The reduced effectiveness of standard-dose influenza vaccines in persons ≥65 years of age led to the preferential recommendation to use high-dose (HDFlu) or MF59-adjuvanted (MF59Flu) vaccines for this age group. Sleep is an important modulator of immune responses to vaccines and poor sleep health is common in older adults. However, potential effects of poor sleep health on immune responses to influenza vaccination in older adults remain largely unknown. Methods: We conducted a cohort study of 210 healthy participants age ≥65 years, who received either seasonal high-dose (HDFlu) or MF59-adjuvanted (MF59Flu) influenza vaccine. We assessed sleep characteristics in this cohort by standardized questionnaires and measured the antibody titer against influenza A/H3N2 virus in serum of study participants by hemagglutination inhibition assay on the day of immunization and 28 days thereafter. We then assessed the association between sleep characteristics and antibody titers. Results: Our results demonstrated that male, but not female, study participants with excessive daytime sleepiness had an impaired influenza A/H3N2-specific antibody response at Day 28 post-vaccination. No other associations were found between antibody titer and other sleep characteristics, including sleep quality and obstructive sleep apnea. Conclusion: Our results provide an additional and easily measured variable explaining poor vaccine effectiveness in older adults. Our results support that gaining sufficient sleep is a simple non-vaccine interventional approach to improve influenza immune responses in older adults. Our findings extend the literature on the negative influence of excessive daytime sleepiness on immune responses to influenza vaccination in older male adults.

Development of vaccines against Zika virus

Zika virus is an emerging pathogen of substantial public health concern to human beings. Although most infections are asymptomatic or present with benign, self-limited symptoms, a small percentage of patients have complications, such as congenital anomalies in the developing fetus of pregnant women infected with the virus and neurological complications (eg, Guillain-Barre syndrome). To date, there is no vaccine, antiviral drug, or other modality available to prevent or treat Zika virus infection. In this Review, we examine vaccine development efforts for Zika virus to date and research gaps in the development of candidate vaccines against Zika virus. Top research priorities should include development of a better understanding of immunity to Zika virus to establish clear correlates of protection; determination of what effect, if any, Zika vaccine-induced immune responses will have on subsequent dengue virus infection; evaluation of vaccine immunogenicity and efficacy in healthy adults and in the various subpopulations affected by Zika virus infection (children, pregnant women, women of childbearing age, and eldery people); and identification of the molecular mechanisms that underlie birth defects and neurological sequelae related to Zika virus.

Development of vaccines against Zika virus

Zika virus is an emerging pathogen of substantial public health concern to human beings. Although most infections are asymptomatic or present with benign, self-limited symptoms, a small percentage of patients have complications, such as congenital anomalies in the developing fetus of pregnant women infected with the virus and neurological complications (eg, Guillain-Barre syndrome). To date, there is no vaccine, antiviral drug, or other modality available to prevent or treat Zika virus infection. In this Review, we examine vaccine development efforts for Zika virus to date and research gaps in the development of candidate vaccines against Zika virus. Top research priorities should include development of a better understanding of immunity to Zika virus to establish clear correlates of protection; determination of what effect, if any, Zika vaccine-induced immune responses will have on subsequent dengue virus infection; evaluation of vaccine immunogenicity and efficacy in healthy adults and in the various subpopulations affected by Zika virus infection (children, pregnant women, women of childbearing age, and eldery people); and identification of the molecular mechanisms that underlie birth defects and neurological sequelae related to Zika virus.