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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Trends in the administration of COVID-19 vaccines with other vaccines in the United States reported to V-safe during December 14, 2020—May 19, 2023

Introduction COVID-19 vaccines may be administered with other vaccines during the same healthcare visit. COVID-19 monovalent (Fall 2021) and bivalent (Fall 2022) vaccine recommendations coincided with annual seasonal influenza vaccination. Data describing the frequency of the co-administration of COVID-19 vaccines with other vaccines are limited. Methods We used V-safe, a voluntary smartphone-based U.S. safety surveillance system established by the CDC, to describe trends in the administration of COVID-19 vaccines with other vaccines reported to V-safe during December 14, 2020 – May 19, 2023. Results Of the 21 million COVID-19 vaccinations reported to V-safe, 2.2% (459,817) were administered with at least 1 other vaccine. Co-administration most frequently occurred during the first week of October 2023 (27,092; 44.1%). Most reports of co-administration included influenza vaccine (393,003; 85.5%). Co-administration was most frequently reported for registrants aged 6 months-6 years (4,872; 4.4%). Conclusion Reports of co-administration to V-safe peaked during October 2023, when influenza vaccination most often occurs, possibly reflecting increased opportunities for multiple vaccinations and greater acceptability of the co-administration of COVID-19 vaccine with other vaccines, especially influenza vaccine.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Bivalent hemagglutinin and neuraminidase influenza replicon particle vaccines protect pigs against influenza a virus without causing vaccine associated enhanced respiratory disease

Alphavirus-derived RNA replicon particle (RP) vaccines represent the next generation of swine influenza A virus (IAV) vaccines, as they were shown to be safe, effective, and offer advantages over traditional vaccine platforms. IAV is a significant respiratory pathogen of swine and there is a critical need to improve current commercial swine IAV vaccine platforms. Adjuvanted whole inactivated virus (WIV) IAV swine vaccines provide limited heterologous protection and may lead to vaccine-associated enhanced respiratory disease (VAERD). This study investigated the ability of RP IAV hemagglutinin (HA) vaccines to avoid VAERD and evaluated experimental multivalent HA and neuraminidase (NA) RP vaccines. RP vaccines were formulated with HA or NA heterologous or homologous to the challenge virus in monovalent HA or HA and NA bivalent combinations (HA/NA bivalent). Pigs were vaccinated with an HA RP, HA/NA bivalent RP, or heterologous HA WIV, followed by IAV challenge and necropsy 5 days post infection. RP vaccines provided homologous protection from challenge and induced robust peripheral and local antibody responses. The RP vaccine did not induce VAERD after challenge with a virus containing the heterologous HA, in contrast to the traditional WIV vaccine. The HA monovalent and HA/NA bivalent RP vaccines showed superior protection compared to traditional WIV. Additionally, the RP platform allows greater flexibility to adjust HA and NA content to reflect circulating IAV in swine antigenic diversity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Addressing Parental Vaccine Hesitancy and Other Barriers to Childhood/Adolescent Vaccination Uptake During the Coronavirus (COVID-19) Pandemic

Routine childhood immunizations are proven to be one of the most effective public health interventions at controlling numerous deadly diseases. Therefore, the CDC recommends routine immunizations for children and adolescent populations against vaccine-preventable diseases e.g., tetanus, pertussis, diphtheria, etc. This current review sought to examine barriers to pediatric vaccine uptake behaviors during the COVID-19 pandemic. We also explored the implications for parental vaccine hesitancy/delay during an ongoing health crisis and proposed recommendations for increasing vaccine confidence and compliance. Our review determined that the receipt for vaccinations steadily improved in the last decade for both the United States and Tennessee. However, this incremental progress has been forestalled by the COVID-19 pandemic and other barriers i.e. parental vaccine hesitancy, social determinants of health (SDoH) inequalities, etc. which further exacerbate vaccination disparities. Moreover, non-compliance to routine vaccinations could cause an outbreak of diseases, thereby, worsening the ongoing health crisis and already strained health care system. Healthcare providers are uniquely positioned to offer effective recommendations with presumptive languaging to increase vaccination rates, as well as, address parental vaccine hesitancy. Best practices that incorporate healthcare providers’ quality improvement coaching, vaccination reminder recall systems, adherence to standardized safety protocols (physical distancing, hand hygiene practices, etc.), as well as, offer telehealth and outdoor/drive-through/curbside vaccination services, etc. are warranted. Additionally, a concerted effort should be made to utilize public health surveillance systems to collect, analyze, and interpret data, thereby, ensuring the dissemination of timely, accurate health information for effective health policy decision-making e.g., vaccine distribution, etc.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Differentiating Vaccine-Related Fowl Cholera from Naturally Occurring Disease

Vaccine-related fowl cholera must be considered when flock mortality increases after use of a live Pasteurella multocida vaccine product. All registered live vaccines serotype as Heddleston 3,4; however, in some regions this is also the most common serotype of outbreak isolates in broiler breeders and turkeys. Therefore, serotyping may not be useful for diagnosing vaccine-related fowl cholera. This project sought to apply a vaccine-specific test to differentiate vaccine-related disease from naturally occurring outbreaks. Results indicate that vaccine strains were commonly isolated from broiler breeders exhibiting signs of fowl cholera post vaccination, but some of these isolates exhibited only serotype 4 antigenicity. The isolates’ lipopolysaccharides, the target antigen for serotyping, contained compositional changes that may explain the varying serotype results and virulence of the commercial preparations. Furthermore, these results suggest that vaccine-related disease may be common in broiler breeders, and live commercial vaccine preparations need to be assessed for serotype and titer prior to use in order to reduce vaccine-related fowl cholera.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

A consensus mathematical model of vaccine-induced antibody dynamics for multiple vaccine platforms and pathogens

Introduction: Vaccine platforms used in successful, licensed vaccines have varied among pathogens. However, antibody level is still the main clinical correlate of protection in most approved vaccines. Decisions as to the best vaccine platform to pursue for a given pathogen may be informed through improved understanding of the process of antibody generation and its temporal dynamics, as well as the relationship between these processes and the type of vaccine. Methods: We have analyzed the dynamics of antibody generation for different vaccine platforms against diverse pathogens, and developed a consensus mathematical model that captures antibody dynamics across these diverse systems. Initially, the model was fitted to a rich dataset of antibody and immune cell concentrations in a SARS-CoV-2 vaccine experiment. We then used concepts from machine learning, such as transfer learning, to apply the same model to a variety of systems, involving different pathogens, vaccine platforms, and booster dose use/timing, fixing most parameter values relating to the dynamics of the immune system. Results: The model includes B cell proliferation and differentiation, as well as the generation of plasma cells, which secrete large amounts of antibody, and memory B cells. Overall, the model describes antibody generation in all systems tested well and shows that the main differences across platforms are related to the dynamics of antigen presentation. Discussion: This model can be used to predict antibody generation in pairs of vaccine platform/pathogen, allowing for the use of in silico results to narrow down experimental burden in vaccine development.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Response to Bovine Viral Diarrhea Virus in Heifers Vaccinated with a Combination of Multivalent Modified Live and Inactivated Viral Vaccines

Bovine viral vaccines contain both live or inactivated/killed formulations, but few studies have evaluated the impact of vaccinating with either live or killed antigens and re-vaccinating with the reciprocal. Commercial dairy heifers were utilized for the study and randomly assigned to three treatment groups. Treatment groups received a commercially available modified-live viral (MLV) vaccine containing BVDV and were revaccinated with a commercially available killed viral (KV) vaccine containing BVDV, another group received the same KV vaccine and was revaccinated with the same MLV vaccine, and yet another group served as negative controls and did not receive any viral vaccines. Heifers in KV/MLV had higher virus neutralizing titers (VNT) at the end of the vaccination period than heifers in MLV/KV and control groups. The frequency of IFN-γ mRNA positive CD4+, CD8+, and CD335+ populations, as well as increased mean fluorescent intensity of CD25+ cells was increased for the MLV/KV heifers as compared to KV/MLV and controls. The data from this study would suggest that differences in initial antigen presentation such as live versus killed could augment CMI and humoral responses and could be useful in determining vaccination programs for optimizing protective responses, which is critical for promoting lifetime immunity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Deletion of the EP402R Gene from the Genome of African Swine Fever Vaccine Strain ASFV-G-ΔI177L Provides the Potential Capability of Differentiating between Infected and Vaccinated Animals

The African swine fever virus (ASFV) mutant ASFV-G-ΔI177L is a safe and efficacious vaccine which induces protection against the challenge of its parental virus, the Georgia 2010 isolate. Although a genetic DIVA (differentiation between infected and vaccinated animals) assay has been developed for this vaccine, still there is not a serological DIVA test for differentiating between animals vaccinated with ASFV-G-ΔI177L and those infected with wild-type viruses. In this report, we describe the development of the ASFV-G-ΔI177L mutant having deleted the EP402R gene, which encodes for the viral protein responsible for mediating the hemadsorption of swine erythrocytes. The resulting virus, ASFV-G-ΔI177L/ΔEP402R, does not have a decreased ability to replicates in swine macrophages when compared with the parental ASFV-G-ΔI177L. Domestic pigs intramuscularly (IM) inoculated with either 10 2 or 10 6 HAD 50 of ASFV-G-ΔI177L/ΔEP402R remained clinically normal, when compared with a group of mock-vaccinated animals, indicating the absence of residual virulence. Interestingly, an infectious virus could not be detected in the blood samples of the ASFV-G-ΔI177L/ΔEP402R-inoculated animals in either group at any of the time points tested. Furthermore, while all of the mock-inoculated animals presented a quick and lethal clinical form of ASF after the intramuscular inoculation challenge with 10 2 HAD 50 of highly virulent parental field isolate Georgia 2010 (ASFV-G), all of the ASFV-G-ΔI177L/ΔEP402R-inoculated animals were protected, remaining clinically normal until the end of the observational period. Most of the ASFV-G-ΔI177L/ΔEP402R-inoculated pigs developed strong virus-specific antibody responses against viral antigens, reaching maximum levels at 28 days post inoculation. Importantly, all of the sera collected at that time point in the ASFV-G-ΔI177L/ΔEP402R-inoculated pigs did not react in a direct ELISA coated with the recombinant EP402R protein. Conversely, the EP402R protein was readily recognized by the pool of sera from the animals immunized with recombinant live attenuated vaccine candidates ASFV-G-ΔI177L, ASFV-G-ΔMGF, or ASFV-G-Δ9GL/ΔUK. Therefore, ASFV-G-ΔI177L/ΔEP402R is a novel, safe and efficacious candidate with potential to be used as an antigenically DIVA vaccine.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Structural and genetic convergence of HIV-1 neutralizing antibodies in vaccinated non-human primates

A primary goal of HIV-1 vaccine development is the consistent elicitation of protective, neutralizing antibodies. While highly similar neutralizing antibodies (nAbs) have been isolated from multiple HIV-infected individuals, it is unclear whether vaccination can consistently elicit highly similar nAbs in genetically diverse primates. Here, we show in three outbred rhesus macaques that immunization with Env elicits a genotypically and phenotypically conserved nAb response. From these vaccinated macaques, we isolated four antibody lineages that had commonalities in immunoglobulin variable, diversity, and joining gene segment usage. Atomic-level structures of the antigen binding fragments of the two most similar antibodies showed nearly identical paratopes. The Env binding modes of each of the four vaccine-induced nAbs were distinct from previously known monoclonal HIV-1 neutralizing antibodies, but were nearly identical to each other. The similarities of these antibodies show that the immune system in outbred primates can respond to HIV-1 Env vaccination with a similar structural and genotypic solution for recognizing a particular neutralizing epitope. These results support rational vaccine design for HIV-1 that aims to reproducibly elicit, in genetically diverse primates, nAbs with specific paratope structures capable of binding conserved epitopes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Reducing Sample Size While Improving Equity in Vaccine Clinical Trials: A Machine Learning-Based Recruitment Methodology with Application to Improving Trials of Hepatitis C Virus Vaccines in People Who Inject Drugs

Despite the availability of direct-acting antivirals that cure individuals infected with the hepatitis C virus (HCV), developing a vaccine is critically needed in achieving HCV elimination. HCV vaccine trials have been performed in populations with high incidence of new HCV infection such as people who inject drugs (PWID). Developing strategies of optimal recruitment of PWID for HCV vaccine trials could reduce sample size, follow-up costs and disparities in enrollment. We investigate trial recruitment informed by machine learning and evaluate a strategy for HCV vaccine trials termed PREDICTEE—Predictive Recruitment and Enrichment method balancing Demographics and Incidence for Clinical Trial Equity and Efficiency. PREDICTEE utilizes a survival analysis model applied to trial candidates, considering their demographic and injection characteristics to predict the candidate’s probability of HCV infection during the trial. The decision to recruit considers both the candidate’s predicted incidence and demographic characteristics such as age, sex, and race. We evaluated PREDICTEE using in silico methods, in which we first generated a synthetic candidate pool and their respective HCV infection events using HepCEP, a validated agent-based simulation model of HCV transmission among PWID in metropolitan Chicago. We then compared PREDICTEE to conventional recruitment of high-risk PWID who share drugs or injection equipment in terms of sample size and recruitment equity, with the latter measured by participation-to-prevalence ratio (PPR) across age, sex, and race. Comparing conventional recruitment to PREDICTEE found a reduction in sample size from 802 (95%: 642–1010) to 278 (95%: 264–294) with PREDICTEE, while also reducing screening requirements by 30%. Simultaneously, PPR increased from 0.475 (95%: 0.356–0.568) to 0.754 (95%: 0.685–0.834). Even when targeting a dissimilar maximally balanced population in which achieving recruitment equity would be more difficult, PREDICTEE is able to reduce sample size from 802 (95%: 642–1010) to 304 (95%: 288–322) while improving PPR to 0.807 (95%: 0.792–0.821). PREDICTEE presents a promising strategy for HCV clinical trial recruitment, achieving sample size reduction while improving recruitment equity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

A Highly Effective African Swine Fever Virus Vaccine Elicits a Memory T Cell Response in Vaccinated Swine

African Swine Fever Virus (ASFV) is the causative agent of a highly contagious and lethal vector-borne disease in suids. Recently, a live attenuated virus strain, developed using the currently circulating, virulent Georgia strain (ASFV-G) with a single gene deletion (ASFV-G-ΔI177L), resulted in an effective vaccine. Nevertheless, protective immune response mechanisms induced by this candidate are poorly understood. In this study, Yorkshire crossbred swine intramuscularly vaccinated with 10 6 50% hemadsorption dose (HAD 50 ) of ASFV-G-ΔI177L or a vehicle control were challenged at 28 days post-inoculation (dpi) with 10 2 HAD 50 of ASFV-G. Analysis of purified peripheral blood mononuclear cells following inoculation and challenge revealed that CD4+, CD8+ and CD4+CD8+ central memory T cells (CD44+CD25–CD27–CD62L+CCR7+, T cm ) decreased significantly by 28 dpi in ASFV-G-ΔI177L-vaccinated swine compared to baseline and time-matched controls. Conversely, CD4+, CD8+ and CD4+CD8+ effector memory T cells (CD44+CD25–CD27–CD62–CCR7–, T em ) increased significantly among ASFV-G-ΔI177L-vaccined swine by 28 dpi compared to baseline and time-matched controls. Additionally, the percentage of natural killer (NK), CD4+ and CD4+CD8+ T em and CD8+ T cm and T em positive for IFNγ increased significantly following inoculation, surpassing that of controls by 28 dpi or earlier. These results suggest that NK and memory T cells play a role in prote

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Single-dose mucosal replicon-particle vaccine protects against lethal Nipah virus infection up to 3 days after vaccination

Nipah virus (NiV) causes a highly lethal disease in humans who present with acute respiratory or neurological signs. No vaccines against NiV have been approved to date. Here, we report on the clinical impact of a novel NiV-derived nonspreading replicon particle lacking the fusion (F) protein gene (NiVΔF) as a vaccine in three small animal models of disease. A broad antibody response was detected that included immunoglobulin G (IgG) and IgA subtypes with demonstrable Fc-mediated effector function targeting multiple viral antigens. Single-dose intranasal vaccination up to 3 days before challenge prevented clinical signs and reduced virus levels in hamsters and immunocompromised mice; decreases were seen in tissues and mucosal secretions, critically decreasing potential for virus transmission. This virus replicon particle system provides a vital tool to the field and demonstrates utility as a highly efficacious and safe vaccine candidate that can be administered parenterally or mucosally to protect against lethal Nipah disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Monomeric crystal structure of the vaccine carrier protein CRM 197 and implications for vaccine development

CRM 197 is a genetically detoxified mutant of diphtheria toxin (DT) that is widely used as a carrier protein in conjugate vaccines. Protective immune responses to several bacterial diseases are obtained by coupling CRM 197 to glycans from these pathogens. Wild-type DT has been described in two oligomeric forms: a monomer and a domain-swapped dimer. Their proportions depend on the chemical conditions and especially the pH, with a large kinetic barrier to interconversion. A similar situation occurs in CRM 197 , where the monomer is preferred for vaccine synthesis. Despite 30 years of research and the increasing application of CRM 197 in conjugate vaccines, until now all of its available crystal structures have been dimeric. Here, CRM 197 was expressed as a soluble, intracellular protein in an Escherichia coli strain engineered to have an oxidative cytoplasm. The purified product, called EcoCRM, remained monomeric throughout crystallization. The structure of monomeric EcoCRM is reported at 2.0 Å resolution with the domain-swapping hinge loop (residues 379–387) in an extended, exposed conformation, similar to monomeric wild-type DT. The structure enables comparisons across expression systems and across oligomeric states, with implications for monomer–dimer interconversion and for the optimization of conjugation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Structural basis of broad HIV neutralization by a vaccine-induced cow antibody

Potent broadly neutralizing antibodies (bnAbs) to HIV have been very challenging to elicit by vaccination in wild-type animals. Here, by x-ray crystallography, cryo–electron microscopy, and site-directed mutagenesis, we structurally and functionally elucidate the mode of binding of a potent bnAb (NC-Cow1) elicited in cows by immunization with the HIV envelope (Env) trimer BG505 SOSIP.664. The exceptionally long (60 residues) third complementarity-determining region of the heavy chain (CDR H3) of NC-Cow1 forms a mini domain (knob) on an extended stalk that navigates through the dense glycan shield on Env to target a small footprint on the gp120 CD4 receptor binding site with no contact of the other CDRs to the rest of the Env trimer. These findings illustrate, in molecular detail, how an unusual vaccine-induced cow bnAb to HIV Env can neutralize with high potency and breadth.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

A human antibody epitope map of Pfs230D1 derived from analysis of individuals vaccinated with a malaria transmission-blocking vaccine

Pfs230 domain 1 (Pfs230D1) is an advanced malaria transmission-blocking vaccine antigen demonstrating high functional activity in clinical trials. However, the structural and functional correlates of transmission-blocking activity are not defined. Here, we characterized a panel of human monoclonal antibodies (hmAbs) elicited in vaccinees immunized with Pfs230D1. These hmAbs exhibited diverse transmission-reducing activity, yet all bound to Pfs230D1 with nanomolar affinity. We compiled epitope-binning data for seventeen hmAbs and structures of nine hmAbs complexes to construct a high-resolution epitope map and revealed that potent transmission-reducing hmAbs bound to one face of Pfs230D1, while non-potent hmAbs bound to the opposing side. The structure of Pfs230D1D2 revealed that non-potent transmission-reducing epitopes were occluded by the second domain. The hmAb epitope map delineated binary hmAb combinations that synergized for extremely high-potency, transmission-reducing activity. Finally, this work provides a high-resolution guide for structure-based design of enhanced immunogens and informs diagnostics that measure the transmission-reducing response.

60 APPLIED LIFE SCIENCES↗