Stand-alone Vaccine Research Articles

An intranasal combination vaccine induces systemic and mucosal immunity against COVID-19 and influenza

Despite prolonged surveillance and interventions, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses continue to pose a severe global health burden. Thus, we developed a chimpanzee adenovirus-based combination vaccine, AdC68-HATRBD, with dual specificity against SARS-CoV-2 and influenza virus. When used as a standalone vaccine, intranasal immunization with AdC68-HATRBD induced comprehensive and potent immune responses consisting of immunoglobin (Ig) G, mucosal IgA, neutralizing antibodies, and memory T cells, which protected the mice from BA.5.2 and pandemic H1N1 infections. When used as a heterologous booster, AdC68-HATRBD markedly improved the protective immune response of the licensed SARS-CoV-2 or influenza vaccine. Therefore, whether administered intranasally as a standalone or booster vaccine, this combination vaccine is a valuable strategy to enhance the overall vaccine efficacy by inducing robust systemic and mucosal immune responses, thereby conferring dual lines of immunological defenses for these two viruses.

Reassessing potential economic value and health impact of effective Shigella vaccines.

The gram-negative bacterium Shigella is a leading cause of diarrheal morbidity and mortality in children in low- and middle-income countries. Several promising vaccine candidates are in late stages of clinical development against this increasingly antibiotic-resistant pathogen. However, considering the increasingly crowded and costly paediatric immunization schedule, and likely advent of other important new vaccines, it is unclear whether introduction of a Shigella vaccine would represent a high priority for international agencies or health ministries in low- and middle-income countries. To determine whether there is a compelling public health value proposition for a Shigella vaccine, we used the World Health Organization's Full Value of Vaccine Assessment analytic framework and formulated five broad scientific, policy, economic and commercial-related propositions regarding the development of a Shigella vaccine. We also explored the current regulatory, clinical, policy and commercial challenges to a Shigella-containing combination vaccine development and adoption. Through a series of literature reviews, expert consultations, social science field studies and model-based analyses, we addressed each of these propositions. As described in a series of separate publications that are synthesized here, we concluded that the economic and public health value of a Shigella vaccine may be greater than previously recognized, particularly if it is found to also be effective against less severe forms of diarrheal disease and childhood stunting. The decision by pharmaceutical companies to develop a standalone vaccine or a multipathogen combination will be a key factor in determining its relative prioritization by various stakeholders in low- and middle-income countries.

Influence of women empowerment on childhood (12–23 months) immunization coverage: Recent evidence from 17 sub-Saharan African countries

BackgroundThere is a global consensus that child immunization plays an important role in promoting the health and well-being of children. Despite the quintessential role of immunization, not all children receive full immunization coverage. We examined the association between women empowerment and childhood immunization coverage in sub-Saharan Africa (SSA).MethodsThe most recent Demographic and Health Survey data of 17 SSA countries were used for the analysis, with a sample of 19,223. The outcome and exposure variables were full immunization coverage and women empowerment, respectively. Full immunization was computed from percentage of children between the ages of 12 and 23 months who had received the following vaccines at any point in time: one dose of Bacille Calmette–Guérin, three doses of the vaccine protecting against diphtheria, pertussis, and tetanus or the tetravalent/pentavalent vaccine, three doses of the polio vaccine, and one dose of the measles vaccine (either as a standalone measles vaccine or as part of a combination with other immunogens). Women’s empowerment was an index of labour participation, acceptance towards spousal violence, decision-making capacity and general knowledge level. Descriptive analysis and multilevel logistic regression were performed. Results were reported in adjusted odds ratio with a corresponding 95% confidence interval.ResultsThe study found that 56.6% of children were fully immunized. Children of employed mothers were 1.16 times more likely to be fully immunized. Children of mothers with higher acceptance toward violence were less likely to be fully immunized [aOR = 0.90, CI 0.81, 0.99]. The odds of full immunization were higher among children born to mothers with high [aOR = 1.11, CI 1.01, 1.22] decision-making capacity. Higher odds of full immunization were found among children born to mothers with medium [aOR = 1.24, CI 1.13, 1.36] to high [aOR = 1.44, CI 1.27, 1.63] general knowledge level.ConclusionsWe conclude that empowering women through livelihood empowerment interventions can increase their decision-making capacity and foster their resolve to ensure the full immunization of their children. This can be achieved by consciously investing in initiatives such as vocational training programs, job placement services, or support for entrepreneurship initiatives to encourage and support women's workforce participation.

Vaccine value profile for Salmonella enterica serovar Paratyphi A

In Asia, there are an estimated 12 million annual cases of enteric fever, a potentially fatal systemic bacterial infection caused by Salmonella enterica serovars Typhi (STy) and Paratyphi A (SPA). The recent availability of typhoid conjugate vaccines (TCV), an increasing incidence of disease caused by SPA and growing antimicrobial resistance (AMR) across the genus Salmonella makes a bivalent STy/SPA vaccine a useful public health proposition. The uptake of a stand-alone paratyphoid vaccine is likely low thus, there is a pipeline of bivalent STy/SPA candidate vaccines. Several candidates are close to entering clinical trials, which if successful should facilitate a more comprehensive approach for enteric fever control. Additionally, the World Health Organization (WHO) has made advancing the development of vaccines that protect young children and working aged adults against both agents of enteric fever a priority objective.This “Vaccine Value Profile” (VVP) addresses information related predominantly to invasive disease caused by SPA prevalent in Asia. Information is included on stand-alone SPA candidate vaccines and candidate vaccines targeting SPA combined with STy. Out of scope for the first version of this VVP is a wider discussion on the development of a universal Salmonella combination candidate vaccine, addressing both enteric fever and invasive non-typhoidal Salmonella disease, for use globally.This VVP is a detailed, high-level assessment of existing, publicly available information to inform and contextualize the public health, economic, and societal potential of pipeline vaccines and vaccine-like products for SPA. Future versions of this VVP will be updated to reflect ongoing activities such as vaccine development strategies and “Full Vaccine Value Assessment” that will inform the value proposition of an SPA vaccine. This VVP was developed by an expert working group from academia, non-profit organizations, public–private partnerships, and multi-lateral organizations as well as in collaboration with stakeholders from the WHO South-East Asian Region. All contributors have extensive expertise on various elements of the VVP for SPA and collectively aimed to identify current research and knowledge gaps.

Vaccine value profile for enterotoxigenic Escherichia coli (ETEC)

Enterotoxigenic Escherichia coli (ETEC) is one of the leading bacterial causes of diarrhoea, especially among children in low-resource settings, and travellers and military personnel from high-income countries. WHO’s primary strategic goal for ETEC vaccine development is to develop a safe, effective, and affordable ETEC vaccine that reduces mortality and morbidity due to moderate-to-severe diarrhoeal disease in infants and children under 5 years of age in LMICs, as well as the long-term negative health impact on infant physical and cognitive development resulting from infection with this enteric pathogen. An effective ETEC vaccine will also likely reduce the need for antibiotic treatment and help limit the further emergence of antimicrobial resistance bacterial pathogens.The lead ETEC vaccine candidate, ETVAX, has shown field efficacy in travellers and has moved into field efficacy testing in LMIC infants and children. A Phase 3 efficacy study in LMIC infants is projected to start in 2024 and plans for a Phase 3 trial in travellers are under discussion with the U.S. FDA. Licensing for both travel and LMIC indications is projected to be feasible in the next 5–8 years.Given increasing recognition of its negative impact on child health and development in LMICs and predominance as the leading etiology of travellers’ diarrhoea (TD), a standalone vaccine for ETEC is more cost-effective than vaccines targeting other TD pathogens, and a viable commercial market also exists. In contrast, combination of an ETEC vaccine with other vaccines for childhood pathogens in LMICs would maximize protection in a more cost-effective manner than a series of stand-alone vaccines.This ‘Vaccine Value Profile’ (VVP) for ETEC is intended to provide a high-level, holistic assessment of available data to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships, and multi-lateral organizations. All contributors have extensive expertise on various elements of the ETEC VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Virus-like Particle Vaccines and Platforms for Vaccine Development.

Virus-like particles (VLPs) have gained a lot of interest within the past two decades. The use of VLP-based vaccines to protect against three infectious agents-hepatitis B virus, human papillomavirus, and hepatitis E virus-has been approved; they are very efficacious and offer long-lasting immune responses. Besides these, VLPs from other viral infectious agents (that infect humans, animals, plants, and bacteria) are under development. These VLPs, especially those from human and animal viruses, serve as stand-alone vaccines to protect against viruses from which the VLPs were derived. Additionally, VLPs, including those derived from plant and bacterial viruses, serve as platforms upon which to display foreign peptide antigens from other infectious agents or metabolic diseases such as cancer, i.e., they can be used to develop chimeric VLPs. The goal of chimeric VLPs is to enhance the immunogenicity of foreign peptides displayed on VLPs and not necessarily the platforms. This review provides a summary of VLP vaccines for human and veterinary use that have been approved and those that are under development. Furthermore, this review summarizes chimeric VLP vaccines that have been developed and tested in pre-clinical studies. Finally, the review concludes with a snapshot of the advantages of VLP-based vaccines such as hybrid/mosaic VLPs over conventional vaccine approaches such as live-attenuated and inactivated vaccines.

Listeria-vectored multi-antigenic tuberculosis vaccine protects C57BL/6 and BALB/c mice and guinea pigs against Mycobacterium tuberculosis challenge

Mycobacterium tuberculosis (Mtb) infects one-third of the world’s population and is a leading cause of death from a single infectious agent. New TB vaccines are urgently needed to augment immunity conferred by the current modestly protective BCG vaccine. We have developed live attenuated recombinant Listeria monocytogenes (rLm)-vectored TB vaccines expressing five [Mpt64/23.5-EsxH/TB10.4-EsxA/ESAT6-EsxB/CFP10-Ag85B/r30] (rLmMtb5Ag) or nine (additionally EsxN-PPE68-EspA-TB8.4) immunoprotective Mtb antigens (rLmMtb9Ag) and evaluated them for safety, immunogenicity and efficacy as standalone vaccines in two mouse models and an outbred guinea pig model. In immunogenicity studies, rLmMtb5Ag administered subcutaneously induces significantly enhanced antigen-specific CD4+ and CD8+ T-cell responses in C57BL/6 and BALB/c mice, and rLmMtb9Ag induces antigen-specific CD4+ and CD8+ T-cell proliferation in guinea pigs. In efficacy studies, both rLmMtb5Ag and rLmMtb9Ag are safe and protect C57BL/6 and BALB/c mice and guinea pigs against aerosol challenge with highly virulent Mtb. Hence, multi-antigenic rLm vaccines hold promise as new vaccines against TB.

2142. Safety and immunogenicity of COVID Influenza Combination Vaccine

Abstract Background We developed a COVID-Influenza Combination (CIC) vaccine, comprising recombinant SARS-CoV-2 Spike (rS) and quadrivalent influenza hemagglutinin (HA) protein nanoparticles (qNIV), and Matrix-MTM adjuvant. rS/Matrix-M previously demonstrated efficacy against COVID-19 in Phase 3 trials, while qNIV/Matrix-M previously demonstrated induction of broadly cross-reactive antibodies. Here we report preliminary safety and immunogenicity results of a first-ever Phase 1/2 CIC dose-finding trial. Methods Seropositive (COVID-19 vaccinated ≥ 8 weeks prior) participants (N=642) aged 50-70 years were randomized equally, to receive two intramuscular doses, 56 days apart, to 1 of 14 different dose/formulations of CIC using a design of experiments approach (dose range: rS 2.5-22.5ug, HA 5-60ug; and 50ug Matrix-M), or to 1 of 2 reference formulations of either standalone rS with Matrix-M [2 doses] or qNIV with Matrix-M [1 dose only]. Pre- and post-vaccination (Days 0, 28, 56, 70, 84, 182) immunogenicity assessments including SARS-CoV-2 anti-S IgG and influenza HAI antibodies to vaccine-homologous strains. Reactogenicity was assessed 7 days following each dose, and safety outcomes assessed through Day 70. Multiple regression was used to create predictive models to assess antibody response surfaces and for dose optimization. Results All CIC formulations were well tolerated, with a reactogenicity and safety profile generally comparable to standalone rS or qNIV. Regression modelling of post-first dose responses revealed that both rS and HA antigens in a CIC formulation modestly interfered with each other, however, interference was overcome with dose adjustment across a range of rS/HA doses. Specifically, higher rS dose ( >20ug), in a dose dependent fashion, overcame HA interference, closely matching standalone rS IgG reference responses (GMEU 16,818), whereas lower, intermediate HA dose overcame rS interference, closely matching standalone HA reference HAI responses for H3N2 (GMT 145), H1N1 (GMT 134), and B-Victoria (GMT 66); while modestly (at least 34%) lower than the reference B-Yamagata response (GMT 101). Conclusion CIC formulations were well tolerated and immunogenic, with various dose combinations achieving response comparable to standalone vaccines. Disclosures Vivek Shinde, MD, MPH, Novavax Inc.: Stocks/Bonds Wayne Woo, MS, Novavax Inc.: Stocks/Bonds Sharon Liu, n/a, Novavax Inc.: Stocks/Bonds Sara Cook, n/a, Novavax Inc.: Stocks/Bonds Zenaida Santiago, n/a, Novavax Inc.: Stocks/Bonds Susan Neal, n/a, Novavax Inc.: Stocks/Bonds Joyce S. Plested, n/a, Novavax Inc.: Stocks/Bonds Tim Vincent, n/a, Novavax Inc.: Stocks/Bonds Mingzhu Zhu, n/a, Novavax Inc.: Stocks/Bonds Shane Cloney-Clark, n/a, Novavax Inc.: Stocks/Bonds Iksung Cho, MS, Novavax Inc.: Stocks/Bonds Lou Fries, n/a, Novavax Inc.: Stocks/Bonds Greg Glenn, n/a, Novavax Inc.: Stocks/Bonds.

SARS-CoV-2 Vaccines: The Mucosal Immunity Imperative

SARS-CoV-2 Vaccines: The Mucosal Immunity Imperative

A Novel Recombinant Influenza Virus Neuraminidase Vaccine Candidate Stabilized by a Measles Virus Phosphoprotein Tetramerization Domain Provides Robust Protection from Virus Challenge in the Mouse Model.

ABSTRACTCurrent seasonal influenza virus vaccines do not induce robust immune responses to neuraminidase. Several factors, including immunodominance of hemagglutinin over neuraminidase, instability of neuraminidase in vaccine formulations, and variable, nonstandardized amounts of neuraminidase in the vaccines, may contribute to this effect. However, vaccines that induce strong antineuraminidase immune responses would be beneficial, as they are highly protective. Furthermore, antigenic drift is slower for neuraminidase than for hemagglutinin, potentially providing broader coverage. Here, we designed stabilized recombinant versions of neuraminidase by replacing the N-terminal cytoplasmic domain, transmembrane, and extracellular stalk with tetramerization domains from the measles or Sendai virus phosphoprotein or from an Arabidopsis thaliana transcription factor. The measles virus tetramerization domain-based construct, termed N1-MPP, was chosen for further evaluation, as it retained antigenicity, neuraminidase activity, and structural integrity and provided robust protection in vivo against lethal virus challenge in the mouse model. We tested N1-MPP as a standalone vaccine, admixed with seasonal influenza virus vaccines, or given with seasonal influenza virus vaccines but in the other leg of the mouse. Admixture with different formulations of seasonal vaccines led to a weak neuraminidase response, suggesting a dominant effect of hemagglutinin over neuraminidase when administered in the same formulation. However, administration of neuraminidase alone or with seasonal vaccine administered in the alternate leg of the mouse induced robust antibody responses. Thus, this recombinant neuraminidase construct is a promising vaccine antigen that may enhance and broaden protection against seasonal influenza viruses.

SARS-COV-2 recombinant Receptor-Binding-Domain (RBD) induces neutralizing antibodies against variant strains of SARS-CoV-2 and SARS-CoV-1

SARS-CoV-2 is the etiological agent of COVID19. There are currently several licensed vaccines approved for human use and most of them target the spike protein in the virion envelope to induce protective immunity. Recently, variants that spread more quickly have emerged. There is evidence that some of these variants are less sensitive to neutralization in vitro, but it is not clear whether they can evade vaccine induced protection. In this study, we tested SARS-CoV-2 spike RBD as a vaccine antigen and explored the effect of formulation with Alum/MPLA or AddaS03 adjuvants. Our results show that RBD induces high titers of neutralizing antibodies and activates strong cellular immune responses. There is also significant cross-neutralization of variants B.1.1.7 and B.1.351 and to a lesser extent, SARS-CoV-1. These results indicate that recombinant RBD can be a viable candidate as a stand-alone vaccine or as a booster shot to diversify our strategy for COVID19 protection.

Health Impact and Cost-effectiveness Assessment for the Introduction of Universal Varicella Vaccination in Switzerland.

Varicella, caused by the varicella-zoster virus, is a highly contagious infectious disease with substantial health and economic burden to society. Universal varicella vaccination (UVV) is not yet recommended by the Swiss National Immunization Program, which instead recommends catch-up immunization for children, adolescents and adults 11-40 years of age who have no reliable history of varicella or are varicella-zoster virus-IgG seronegative. The objective of this study was to perform an assessment of health impact and cost-effectiveness comparing UVV with current practice and recommendations in Switzerland. A dynamic transmission model for varicella was adapted to Switzerland comparing 2 base-case schedules (no infant vaccination and 10% coverage with infant vaccination) to 3 different UVV schedules using quadrivalent (varicella vaccine combined with measles-mumps-rubella) and standalone varicella vaccines administered at different ages. Modeled UVV coverage rates were based on current measles-mumps-rubella coverage of approximately 95% (first dose) and 90% (second dose). Direct medical costs and societal perspectives were considered, with cost and outcomes discounted and calculated over a 50-year time horizon. UVV would reduce the number of varicella cases by 88%-90%, hospitalizations by 62%-69% and deaths by 75%-77%. UVV would increase direct medical costs by Swiss Franc (CHF) 39-49 (US $43-54) per capita and costs from a societal perspective by CHF 32-40 (US $35-44). Incremental quality-adjusted life-years per capita increased by 0.0012-0.0014. Incremental cost-effectiveness ratios for the UVV schedules versus the base-case were CHF 31,194-35,403 (US $34,452-39,100) per quality-adjusted life-year from the direct medical cost perspective and CHF 25,245-29,552 (US $27,881-32,638) from the societal perspective. UVV appears highly effective and cost-effective when compared with current clinical practice and recommendations in Switzerland from both a direct medical costs perspective and societal perspective.

Immunological characterization of chimeras of high specificity antigens from Mycobacterium tuberculosis H37Rv

Tuberculosis remains a serious global health problem. BCG is the only prophylactic TB vaccine and it shows variable protective efficacy. Chimeric protein subunit vaccines hold great potential as stand-alone vaccines or heterologous BCG prime boosters. We have designed a protein chimera, PP31, by combining Mtb ESAT-6 family antigen Rv1198 and MoCo biosynthesis family antigen Rv3111. Further, PP31 was extended by addition of latency antigen Rv1813c to yield PP43. Immunization of BALB/c mice with PP31 or PP43 with FIA adjuvant elicited strong humoral immune response. Restimulation of splenocytes of the immunized mice lead to significant proliferation of lymphocytes, secretion of cytokines IFN-γ, TNF, IL-2 of the Th1 class, IL-17A of the Th17 class, and IL-6. PP31 and PP43 also induced intracellular cytokine expression (IFN-γ, TNF, and IL-2) from both CD4+-CD44high and CD8+-CD44high T-cells. Antigen-specific IFN-γ+/IL-2+ double positive CD4+ T-cells were significantly higher in case of PP43 than PP31-immunized mice and control group. PP43 showed protection equivalent to heat-inactivated BCG in response to challenge of the immunized mice with Mtb H37Ra. Based on its immunogenicity and protective efficacy, PP43 appears to be a potential candidate for further development as a subunit vaccine against TB.

DTaP combination vaccine use and adherence: A retrospective cohort study

Despite universal recommendation of the 4-dose diphtheria, tetanus, and pertussis (DTaP) vaccine series, coverage and timeliness in the US remain suboptimal. DTaP-containing combination vaccines (i.e. quadrivalent and pentavalent) are presumed to improve vaccine coverage rates and timeliness, but research supporting this claim is limited. We sought to investigate the associations between DTaP-containing vaccine use and adherence to the recommended DTaP immunization schedule among children in the US. Using a large claims database, we identified privately insured children born between 2009 and 2016 that received ≥1 DTaP-containing vaccine and had ≥24 months of enrollment from birth, excluding those with DTaP vaccinations not aligned with approved dose indications. Children were classified by DTaP-containing vaccine receipt: combination vaccines only, stand-alone vaccines only, or a mixture of both. Outcome measures included: 1) completion of the 4-dose series and 2) timely receipt of doses. Outcomes were adjusted for gender, birth year, race, and socioeconomic status. The study cohort contained 412,441 children. Of these, 40.5% (167,084) received combination vaccines only, 14.9% (61,342) received stand-alone vaccines only, and 44.6% (184,015) received a mixture of both. Combination vaccine recipients were nearly 3 times as likely to complete the 4-dose series (OR 2.93 (95% CI: 2.88, 2.99)) and for all doses received, more than 4 times as likely to receive doses on time (OR 4.12 (4.04, 4.21), relative to stand-alone vaccine recipients. Significance disparities in adherence were also observed, where minorities were up to 30% less likely (OR 0.70 (0.68, 0.71)) to complete the 4-dose series and up to 27% less likely (OR 0.73 (0.72, 0.75)) to receive doses on time, relative to white children. Our findings demonstrated that adherence to the recommended DTaP immunization schedule was significantly greater among combination vaccine recipients, relative to stand-alone recipients. Further research is needed to investigate underlying causes of disparities in adherence.

1388. DTaP-containing combination vaccines use and adherence to the recommended infant-toddler vaccination series among privately insured children in the US

BackgroundDespite universal recommendation of the 3 + 1 diphtheria, tetanus, and pertussis (DTaP) vaccine series in infants and toddlers, adherence (i.e. coverage and timeliness) remain suboptimal in the US. DTaP-containing combination vaccines are presumed to improve vaccine coverage rates and timeliness, but research on this topic is limited. The purpose of this study was to compare adherence to the recommended infant-toddler vaccination series between recipients of DTaP-containing combination vaccines (i.e. quadrivalent/pentavalent) and stand-alone vaccines (i.e. trivalent).MethodsWe used the Optum de-identified Clinformatics Data Mart database to create a cohort of children born between 2009 and 2016 with > 24 months of continuous enrollment from birth, and records of > 1 DTaP vaccine receipt. Patients were classified by DTaP-containing vaccine receipt: combination vaccines only, stand-alone vaccines only, or a mixture of both. The primary adherence outcome was completion of the 4-dose series within 20 months of life. We adjusted outcomes for gender, birth year, race, and socioeconomic status via a logistic regression model.ResultsThe cohort contained 200,568 female (48.6%) and 211,882 male (51.4%) children. Of these children, 167,091 received combination vaccines only (40.5%), 61,342 received stand-alone vaccines only (14.9%), and 184,017 received a mixture of both (44.6%). Completion of the 4-dose series was highest among children who received combination vaccines only (75.5%), followed by those who received a mixture of vaccines (72.7%) and those who received stand-alone vaccines only (54.5%). Relative to those who received stand-alone vaccines only, adjusted odds of completion were approximately 2.9 times higher among combination vaccine recipients (odds ratio, OR = 2.93 [95% CI: 2.87, 2.98]) and 2.5 times higher among those who received a mixture of vaccines (OR = 2.54 [2.49, 2.59]).ConclusionDTaP-containing combination vaccine use was associated with significantly greater adherence. Although these results warrant further investigation to better understand the determinants of infant vaccination adherence, such evidence may further support preferential recommendations for combination vaccine use.DisclosuresMatthew M. Loiacono, MSc, Sanofi Pasteur (Employee) Vitali Pool, MD, Sanofi Pasteur (Employee) Robertus Van Aalst, MSc, Sanofi Pasteur (Employee)

1522. Safety and Efficacy of CR6261 in an Influenza A H1N1 Healthy Human Challenge Model

BackgroundInfluenza virus infections cause significant morbidity and mortality during yearly seasonal epidemics and during sporadic pandemics. It is imperative to identify new targets for vaccines and therapeutics. One such target is the relatively conserved stalk region of the influenza A hemagglutinin (HA) surface protein.MethodsWe conducted a randomized, double-blind, Phase II placebo-controlled trial of a monoclonal antibody that targets the HA stalk (CR6261) in a H1N1pdm09 healthy volunteer human challenge model. CR6261 was infused 24 hours after challenge with H1N1pdm09 and the primary efficacy outcome was area under the curve (AUC) of viral shedding.ResultsBetween March 2015-May 2018, 104 healthy volunteers were enrolled and randomized with 91 undergoing influenza challenge, of which 49 participants (54%) received treatment with CR6261 and 42 participants (46%) received placebo. A mean of 1x106 ng/mL of serum CR6261 was detected by 24 hours after infusion. Nasal CR6261 levels reached a peak mean of 5.97x102 ng/ml 2 days after infusion. There was no statistically significant difference in the primary outcome measure between the CR6261 group and placebo (median AUC 48.56 and 25.53 respectively, P=0.31). The severity of illness was compared between the two groups, and no significant difference was observed in number of symptoms, duration of symptoms, or FLU-PRO scores.ConclusionCR6261 had no statistically significant effect on AUC of viral shedding, and no clinically significant effect on overall influenza disease. Preexisting anti-neuraminidase (NA) antibody titers were most predictive of reduced influenza disease. Nasal CR6261 levels were much lower compared to serum, which may be a factor in the limited effect of CR6261 on this upper respiratory infection. These results suggest that a monoclonal anti-stalk approach to prevent or treat influenza infection may have limited efficacy. Future approaches should consider including and evaluating anti-stalk antibodies as part of a multi-faceted strategy rather than as a standalone therapeutic or vaccine strategy.FundingThis study was funded in part by the intramural program of NIAID, NIH, by the NCI Contract No. 75N910D00024, Task Order No. 75N91019F00130, and through a CRADA with Janssen Infectious Diseases and Vaccines.DisclosuresAmy Lwin, RN, BSN, Janssen Pharmaceutical Company of J&J (Employee) Jerald Sadoff, MD, Janssen Pharmaceutical Company of J&J (Employee)

Abstract PO-049: SARS-CoV-2 multiepitope vaccine constructs designed to drive long-term immunity in the majority of the population

Abstract The current SARS-CoV-2 pandemic has precipitated an urgent need for a safe and effective vaccine to be developed and deployed in a highly accelerated timeframe as compared to standard vaccine development processes. Upfront selection of epitopes most likely to induce a safe and effective immune response can accelerate these efforts. Optimally designed vaccines maximize immunogenicity towards regions of proteins that contribute most to protective immunity, while minimizing the antigenic load contributed by unnecessary protein domains that may result in autoimmunity, reactogenicity, or enhanced infectivity. Adopting tools developed for population-scale characterization of HLA presentation of tumor antigens and cross-reactivity of TCRs with tumor self-antigens, we have generated an immunogenicity map of SARS-CoV-2 to inform vaccine design based on analyses across five parameters: 1) stimulation of CD4 and CD8 T cells; 2) immunogenicity across the majority of human HLA alleles; 3) targeting both evolutionarily conserved regions, as well as newly divergent regions of the virus that increase infectivity; 4) targeting linear and conformational B-cell epitopes; and 5) targeting viral regions with the highest degree of dissimilarity to the self-immunopeptidome such as to maximize safety and immunogenicity. Using these analyses, we have generated 11 SARS-CoV-2 vaccine constructs optimized for long-term immunity across the majority of the population. These constructs contain combinations of epitopes selected from our analysis such as to drive affinity-enhanced memory response in combination with current spike protein vaccine strategies, for use as T-cell vaccines, and a stand-alone vaccine designed to drive memory B- and T-cell responses in the majority of the population. Epitopes were optimized using our immunogenicity algorithm to minimize immunogenicity across the junctions between epitopes and cloned into pVAX vectors, using signal peptides targeting the lysosome, ER, and cytoplasmic secretion, such as to promote presentation to CD4, CD8, and B cells, respectively. Finally, we describe methods for identifying immunodominant epitopes arising from vaccination using barcoded, multiplexed tetramers. Vaccine constructs are currently undergoing testing in transgenic mice expressing human HLA-A2. We expect that these constructs will help drive long-term immunity across the population, targeting conserved regions across multiple coronaviruses. Citation Format: Mark Yarmarkovich, John M. Warrington, Alvin Farrel, John M. Maris. SARS-CoV-2 multiepitope vaccine constructs designed to drive long-term immunity in the majority of the population [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-049.

Comparison of carrier proteins to conjugate malaria transmission blocking vaccine antigens, Pfs25 and Pfs230

Malaria transmission blocking vaccines (TBV) target the sexual stage of the parasite and have been pursued as a stand-alone vaccine or for combination with pre-erythrocytic or blood stage vaccines. Our efforts to develop TBV focus primarily on two antigens, Pfs25 and Pfs230. Chemical conjugation of these poorly immunogenic antigens to carrier proteins enhances their immunogenicity, and conjugates of these antigens to Exoprotein A (EPA) are currently under evaluation in clinical trials. Nonetheless, more potent carriers may augment the immunogenicity of these antigens for a more efficacious vaccine; here, we evaluate a series of proteins to identify such a carrier. Pfs25 and Pfs230 were chemically conjugated to 4 different carriers [tetanus toxoid (TT), a recombinant fragment of tetanus toxin heavy chain (rTThc), recombinant CRM197 produced in Pseudomonas fluorescens (CRM197) or in E. coli (EcoCRM®)] and compared to EPA conjugates in mouse immunogenicity studies. Conjugates of each antigen formulated in Alhydrogel® elicited similar antibody titers but showed differences in functional activity. At a 0.5 µg dose, Pfs230 conjugated to TT, CRM197 and EcoCRM® showed significantly higher functional activity compared to EPA. When formulated with the more potent adjuvant GLA-LSQ, all 4 alternate conjugates induced higher antibody titers as well as increased functional activity compared to the EPA conjugate. IgG subclass analysis of Pfs230 conjugates showed no carrier-dependent differences in the IgG profile. While Alhydrogel® formulations induced a Th2 dominant immune response, GLA-LSQ formulations induced a mixed Th1/Th2 response.

Safety and immunogenicity of experimental stand-alone trivalent, inactivated Sabin-strain polio vaccine formulations in healthy infants: A randomized, observer-blind, controlled phase 1/2 trial

BackgroundTo increase the global supply of affordable IPV vaccine, preferably using Sabin viruses to comply with GAPIII requirements, Takeda has assessed three dosages of a stand-alone sIPV. MethodsIn this phase I/II study two cohorts of 40 adults and 60 toddlers, respectively, were initially assessed for safety after receiving high-dosage sIPV compared with placebo (adults) or Salk IPV (toddlers). A cohort of 240 infants was then enrolled and randomized (1:1:1:1) to receive low-, medium- or high-dosage sIPV, or a reference Salk IPV in a three-dose primary schedule at 6, 10 and 14 weeks of age. Parents completed safety diaries for 4 weeks after each dose, and immunogenicity was measured as neutralization antibody titers at baseline and four weeks after vaccination. ResultsAll vaccinations were generally well-tolerated and sIPV had a comparable safety profile to the control arm in adults or the reference Salk IPV vaccine in toddlers and infants. Infants displayed dosage-dependent immune responses to sIPV when assayed using Sabin strains, which were equivalent to the reference IPV in the high-dosage sIPV group for serotypes 1 and 2, but not for Sabin and Salk serotype 3. Seroconversion rates (SCR) of the low- and medium-dosage groups were significantly lower than the Salk IPV group for both Sabin and Salk serotypes 1 and type 2 (p < 0.05), with no significant differences for Salk or Sabin serotypes 3. Responses to sIPV, particularly to Sabin types 1 and 2, were higher in initially seronegative infants, indicating possible interference by maternally-derived antibodies. ConclusionsA novel stand-alone Sabin-based IPV vaccine was well tolerated with an acceptable safety profile, but less immunogenic than reference Salk IPV at 6, 10 and 14 weeks of age for Salk serotypes 1 and 2, with apparent interference by maternal antibodies. Additional preclinical assessments will be made before any further clinical development.

2698. Timing of Standalone Vaccine Administration in Infants Receiving DTaP-Based Combination Vaccines

BackgroundThe recommended US infant immunization schedule includes doses of DTaP, IPV, Hib and HepB during the first 6 months of life. The majority of infants receive DTaP as one of the two pentavalent combination vaccines (DTaP-IPV/Hib or DTaP-HepB-IPV); standalone HepB or Hib are used to complement these combinations in compliance with the recommendations. Little is known about the timing of standalone vaccine administration in relation to DTaP-based combination vaccines.MethodsThis was a retrospective observational cohort study using the US MarketScan commercial claims and encounters database. Infants included in the study were continuously enrolled in the same insurance plan for ≥13 months after birth, born from 1 July 2010 through 30 June 2016, and had received ≥3 doses of a pentavalent vaccine. Outcomes included the proportion of infants receiving concomitant pentavalent and standalone vaccines, and the deviation in days when these vaccines were not administered on the same date. Birth doses of HepB were not registered in the database but were presumed to have been received; therefore, the first registered HepB claim was considered to be HepB Dose-2, and the second claim was presumed to be HepB Dose-3.ResultsAmong infants who received DTaP-IPV/Hib (n = 175,574), 94.8% had claims for ≥3 doses of HepB. Although coverage was high, only 60.7% received HepB Dose-2 on the same day as DTaP-IPV/Hib Dose-1 (around 2 months of age), and only 45.1% received HepB Dose-3 on the same day as DTaP-IPV/Hib Dose-3 (around 6 months of age) (Figure 1). Many infants (46.2%) received HepB Dose-3 after the third dose of DTaP-IPV/Hib. Among infants who received DTaP-HepB-IPV (n = 97,206), 89.9% had claims for the recommended number of Hib doses; most (91% to 98%) of these doses were administered on the same day as doses of DTaP-HepB-IPV (Figure 2).ConclusionThere was variability in the timing of HepB doses in infants receiving DTaP-IPV/Hib. A newly licensed hexavalent vaccine, DTaP-IPV-Hib-HepB, could synchronize and simplify the HepB administration schedule ensuring that more infants have completed the series by 6 months of age. Disclosures All authors: No reported disclosures.