Vaccine Approaches Research Articles

Navigating the Dynamic Landscape of SARS-CoV-2: The Dual Role of Neutralizing Antibodies, Variability in Responses, and Strategies for Adaptive Pandemic Control

The global pandemic sparked by the emergence of SARS-CoV-2 and its variants has imposed a substantial burden of morbidity and mortality. Central to the battle against these viral threats is the immune response, with a spotlight on the pivotal role played by neutralizing antibodies. This comprehensive review delves into current research, unravelling the dual functionality of neutralizing antibodies acting as formidable barriers to viral replication and crucial facilitators of adaptive immune memory. Beyond this dual purpose, the review illuminates the nuanced variability characterizing neutralizing antibody responses to SARS-CoV-2. Emphasizing the dynamic nature of these responses, the review advocates for the plausible challenges in targeted therapeutic interventions. This review also attempts to compare various vaccination approaches and their impact on SARS-CoV-2, as well as offer insights into various Omicron variations. Recognizing the ever-evolving viral landscape, this exploration underscores the necessity of flexible approaches to address the diverse challenges posed by SARS-CoV-2 and its variants, contributing valuable insights to the ongoing global efforts in pandemic mitigation and public health safeguarding.

Emerging and Biological Concepts in Pediatric High-Grade Gliomas.

Primary central nervous system tumors are the most frequent solid tumors in children, accounting for over 40% of all childhood brain tumor deaths, specifically high-grade gliomas. Compared with pediatric low-grade gliomas (pLGGs), pediatric high-grade gliomas (pHGGs) have an abysmal survival rate. The WHO CNS classification identifies four subtypes of pHGGs, including Grade 4 Diffuse midline glioma H3K27-altered, Grade 4 Diffuse hemispheric gliomas H3-G34-mutant, Grade 4 pediatric-type high-grade glioma H3-wildtype and IDH-wildtype, and infant-type hemispheric gliomas. In recent years, we have seen promising advancements in treatment strategies for pediatric high-grade gliomas, including immunotherapy, CAR-T cell therapy, and vaccine approaches, which are currently undergoing clinical trials. These therapies are underscored by the integration of molecular features that further stratify HGG subtypes. Herein, we will discuss the molecular features of pediatric high-grade gliomas and the evolving landscape for treating these challenging tumors.

Immunoprevention Strategies for Colorectal Cancer in Lynch Syndrome Carriers.

The immune revolution that swept the field of oncology in the mid-2010s with the advent of checkpoint inhibitors has led to a paradigm shift in approaches toward adapting new cancer prevention modalities. Cancer vaccines have emerged from this era with astounding potential as a durable intervention to prevent cancers especially for patients with hereditary susceptibilities such as Lynch syndrome carriers. This review covers new insights in the immunoprevention landscape for patients living with Lynch syndrome including highlights ranging from clinical trials exploring the use of chemoprevention agents to boost immune cellularity to investigative studies using novel vaccine approaches to induce long-term antitumor immunity.

Lipid nanoparticle-encapsulated DNA vaccine confers protection against swine and human-origin H1N1 influenza viruses.

Swine influenza A virus (IAV) is widespread and causes significant economic losses to the swine industry. Moreover, bidirectional transmission of IAV between swine and humans commonly occurs. Once introduced into the swine population, human-origin IAV often reassorts with endemic swine IAV, resulting in reassortant viruses. Thus, it is imperative to develop a vaccine that is not only effective against IAV strains endemic in swine but also capable of preventing the spillover of human-origin IAV. In this study, we developed a lipid nanoparticle-encapsulated DNA plasmid vaccine (LNP-DNA) that demonstrates efficacy against both swine- and human-origin H1N1 viruses. The LNP-DNA vaccines are non-infectious and non-viable, meeting the criteria to serve as a vaccine platform for rapidly updating vaccines. Collectively, this LNP-DNA vaccine approach holds great potential for alleviating the impact of IAV on the swine industry and preventing the emergence of reassortant IAV strains.

A mass cytometry method pairing T cell receptor and differentiation state analysis.

T cell antigen receptor (TCR) recognition followed by clonal expansion is a fundamental feature of adaptive immune responses. Here, we present a mass cytometric (CyTOF) approach to track T cell responses by combining antibodies for specific TCR Vα and Vβ chains with antibodies against T cell activation and differentiation proteins in mice. This strategy identifies expansions of CD8+ and CD4+ T cells expressing specific Vβ and Vα chains with varying differentiation states in response to Listeria monocytogenes, tumors and respiratory influenza infection. Expanded T cell populations expressing Vβ chains could be directly linked to the recognition of specific antigens from Listeria, tumor cells or influenza. In the setting of influenza infection, we found that common therapeutic approaches of intramuscular vaccination or convalescent serum transfer altered the TCR diversity and differentiation state of responding T cells. Thus, we present a method to monitor broad changes in TCR use paired with T cell phenotyping during adaptive immune responses.

Rotavirus Infections: A 2-Year Comprehensive Review in Admitted Pediastric Patients Amid Conflicting National Policies.

Highlighting rotavirus (RV) as a significant food and waterborne pathogen, particularly affecting infants and children, causing serious gastrointestinal infections and dehydration, is important. It should be noted that there are significant debates regarding the effectiveness and outcomes of RV vaccination. In contrast to Turkey's nonmandatory vaccination policy, many developed countries implement mandatory vaccination policies, raising questions about their impact on disease prevalence and healthcare expenditures. Our study aims to comprehensively understand RV infections in Turkey and compare them with countries that have mandatory vaccination policies. We found similar, and even better, hospitalization rates, length of hospital stays, and laboratory parameters demonstrating the effectiveness of Turkey's independent vaccination approach. These findings contribute valuable insights to global vaccination strategies and disease control.

Vaccines for Respiratory Viruses-COVID and Beyond.

The COVID-19 (coronavirus disease 2019) pandemic had an extensive impact on global morbidity and mortality. Several other common respiratory viruses, such as the influenza virus and respiratory syncytial virus (RSV), are endemic or epidemic agents causing acute respiratory infections that are easily transmissible and pose a significant threat to communities due to efficient person-to-person transmission. These viruses can undergo antigenic variation through genetic mutations, resulting in the emergence of novel strains or variants, thereby diminishing the effectiveness of current vaccines, and necessitating ongoing monitoring and adjustment of vaccine antigens. As the virus-specific immunity is maintained only for several weeks or months after the infection, there is an emergent need to develop effective and durable vaccines. Additionally, specific populations, such as elderly or immunocompromised individuals, may exhibit reduced immune responses to respiratory viruses, posing significant challenges to develop vaccines that elicit durable and potent immunity. We present a comprehensive review of the molecular mechanisms underlying the pathogenesis and virulence of common respiratory viruses, such as RSV, influenza virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We discuss several vaccine approaches that are under development. A thorough understanding of the current strategies and the challenges encountered during the vaccine development process can lead to the advancement of effective next-generation vaccines.

Immunogenicity and safety of different combinations involving a third booster dose of SARS-CoV-2 inactivated vaccine, inactivated quadrivalent influenza vaccine, and 23-valent pneumococcal polysaccharide vaccine in adults aged ≥60 years: a phase 4, randomized, open-label study.

Concomitant administration of COVID-19, influenza, and pneumococcal vaccines could reduce the burden on healthcare systems. However, the immunogenicity and safety of various combinations of a third booster dose of SARS-CoV-2 inactivated vaccine (CoronaVac), inactivated quadrivalent influenza vaccine (IIV4), and 23-valent pneumococcal polysaccharide vaccine (PPV23), particularly in different age groups, is still unknown. A phase 4, randomized, open-label, controlled trial was conducted in Beijing, China. 636 healthy adults were divided into two age groups (18-59 and ≥60 years) and randomized equally into three groups: CoronaVac and IIV4 followed by PPV23; CoronaVac and PPV23 followed by IIV4; or CoronaVac followed by IIV4 and PPV23, with a 28-day interval between vaccinations. Immunogenicity was evaluated by measuring antibody titers, and safety was monitored. ClinicalTrials.gov Identifier: NCT05298800. Co-administration of a third dose of CoronaVac, IIV4, and PPV23 in any combination was safe. Among adults aged 18-59, co-administration with PPV23 maintained non-inferiority of antibody levels for CoronaVac and IIV4, despite a slight reduction in antibody responses. This reduction was not observed in participants ≥60 years. Furthermore, co-administration of IIV4 and PPV23 affected seroconversion rates for both vaccines. Co-administration of the third dose of SARS-CoV-2 inactivated vaccine with the influenza vaccine, followed by PPV23, may be optimal for adults aged 18-59. In adults ≥60, all vaccine combinations were immunogenic, suggesting a flexible vaccination approach. Since antibody measurements were taken 28 days post-vaccination, ongoing surveillance is essential to assess the longevity of the immune responses.

Vaccination to Prevent Lyme Disease: A Movement Towards Anti-Tick Approaches.

Lyme disease is caused by the spirochete, Borrelia burgdorferi, which is transmitted by Ixodes spp ticks. The rise in Lyme disease cases since its discovery in the 1970s has reinforced the need for a vaccine. A vaccine based on B burgdorferi outer surface protein A (OspA) was approved by the Food and Drug Administration (FDA) several decades ago, but was pulled from the market a few years later, reportedly due to poor sales, despite multiple organizations concluding that it was safe and effective. Newer OspA-based vaccines are being developed and are likely to be available in the coming years. More recently, there has been a push to develop vaccines that target the tick vector instead of the pathogen to inhibit tick feeding and thus prevent transmission of tick-borne pathogens to humans and wildlife reservoirs. This review outlines the history of Lyme disease vaccines and this movement to anti-tick vaccine approaches.

A self-amplifying RNA vaccine prevents enterovirus D68 infection and disease in preclinical models.

The recent emergence and rapid response to severe acute respiratory syndrome coronavirus 2 was enabled by prototype pathogen and vaccine platform approaches, driven by the preemptive application of RNA vaccine technology to the related Middle East respiratory syndrome coronavirus. Recently, the National Institutes of Allergy and Infectious Diseases identified nine virus families of concern, eight enveloped virus families and one nonenveloped virus family, for which vaccine generation is a priority. Although RNA vaccines have been described for a variety of enveloped viruses, a roadmap for their use against nonenveloped viruses is lacking. Enterovirus D68 was recently designated a prototype pathogen within the family Picornaviridae of nonenveloped viruses because of its rapid evolution and respiratory route of transmission, coupled with a lack of diverse anti-enterovirus vaccine approaches in development. Here, we describe a proof-of-concept approach using a clinical stage RNA vaccine platform that induced robust enterovirus D68-neutralizing antibody responses in mice and nonhuman primates and prevented upper and lower respiratory tract infections and neurological disease in mice. In addition, we used our platform to rapidly characterize the antigenic diversity within the six genotypes of enterovirus D68, providing the necessary data to inform multivalent vaccine compositions that can elicit optimal breadth of neutralizing responses. These results demonstrate that RNA vaccines can be used as tools in our pandemic-preparedness toolbox for nonenveloped viruses.

Experimental vaccination by single dose sporozoite injection of blood-stage attenuated malaria parasites

Malaria vaccination approaches using live Plasmodium parasites are currently explored, with either attenuated mosquito-derived sporozoites or attenuated blood-stage parasites. Both approaches would profit from the availability of attenuated and avirulent parasites with a reduced blood-stage multiplication rate. Here we screened gene-deletion mutants of the rodent parasite P. berghei and the human parasite P. falciparum for slow growth. Furthermore, we tested the P. berghei mutants for avirulence and resolving blood-stage infections, while preserving sporozoite formation and liver infection. Targeting 51 genes yielded 18 P. berghei gene-deletion mutants with several mutants causing mild infections. Infections with the two most attenuated mutants either by blood stages or by sporozoites were cleared by the immune response. Immunization of mice led to protection from disease after challenge with wild-type sporozoites. Two of six generated P. falciparum gene-deletion mutants showed a slow growth rate. Slow-growing, avirulent P. falciparum mutants will constitute valuable tools to inform on the induction of immune responses and will aid in developing new as well as safeguarding existing attenuated parasite vaccines.

Community-based COVID-19 vaccination services improve user satisfaction: findings from a large household survey in Bali Province, Indonesia.

Background Understanding community preferences for vaccination services is crucial for improving coverage and satisfaction. There are three main approaches for COVID-19 vaccination in Indonesia: health facility-based, community-based, and outreach approaches. This study aims to assess how the vaccination approaches impact user satisfaction levels. Methods This study was part of a large household survey involving 12,120 respondents across nine districts in Bali Province. The study population comprised all residents aged ≥12years who had received at least one dose of COVID-19 vaccination. Samples were selected through three stages of systematic random sampling. Data were collected through interviews using structured questionnaires, which included socio-demographic characteristics, vaccination services, and satisfaction levels. Analysis was performed using Chi Square test and logistic regression, with the entire process incorporating weighting factors. Results A total of 12,120 respondents reported receiving their first dose of COVID-19 vaccination. The satisfaction level among vaccine recipients (partial, complete, and booster doses) was high (84.31%). Satisfaction within each SERVQUAL dimension was highest in tangibles (96.10%), followed by responsiveness (93.25%), empathy (92.48%), assurance (92.35%), and reliability (92.32%). There was no significant difference in the overall SERVQUAL score between the health facility and community-based approaches. However, the latter slightly improved user satisfaction across three dimensions: tangibles (adjusted odds ratio, AOR=1.52, 95% confidence interval (CI)=1.21-1.90), reliability (AOR=1.67, 95%CI=1.42-1.96), and assurance (AOR=1.26, 95%CI=1.07-1.48). Conclusion During the pandemic, both health facility and community-based approaches resulted in a high satisfaction level. It is recommended that the government prioritise and optimise community-based programs and health facility-based delivery in future vaccination initiatives, especially during public health emergencies.

Immunoinformatics approach for design novel multi-epitope prophylactic and therapeutic vaccine based on capsid proteins L1 and L2 and oncoproteins E6 and E7 of human papillomavirus 16 and human papillomavirus 18 against cervical cancer.

This study aimed to identify the optimal protein construction for designing a multi-epitope vaccine with both prophylactic and therapeutic effects against cervical cancer, utilizing an immunoinformatics approach. The construction process involved using capsid epitopes L1 and L2, as well as oncoproteins E5, E6, and E7 from human papillomavirus (HPV) types 16 and 18. An experimental in silico analysis with an immunoinformatics approach was used to develop 2 multi-epitope vaccine constructs (A and B). Further analysis was then conducted to compare the constructs and select the one with the highest potential against cervical cancer. This study produced 2 antigenic, non-allergenic, and nontoxic multi-epitope vaccine constructs (A and B), which exhibited the ideal physicochemical properties for a vaccine. Further analysis revealed that construct B effectively induced both cellular and humoral immune responses. The multi-epitope vaccine construct B for HPV 16 and 18, designed for both prophylactic and therapeutic purposes, met the development criteria for a cervical cancer vaccine. However, these findings need to be validated through in vitro and in vivo experiments.

UL56 Is Essential for Herpes Simplex Virus-1 Virulence In Vivo but Is Dispensable for Induction of Host-Protective Immunity.

Herpes simplex virus-1 (HSV-1) is common and can cause significant disease in humans. Unfortunately, efforts to develop effective vaccines against HSV-1 have so far failed. A detailed understanding of how the virus infects its host and how the host mounts potent immune responses against the virus may inform new vaccine approaches. Here, using a zosteriform mouse model, we examined how the HSV-1 gene UL56 affects the ability of the virus to cause morbidity and generate protective immunity. A UL56 deletion mutant, ΔUL56, was derived from the wild-type HSV-1 strain SC16, alongside a revertant strain in which UL56 was reintroduced in ΔUL56. In vitro, the three virus strains replicated in a similar manner; however, in vivo, only the wild type and the revertant strains caused shingles-like skin lesions and death. Mice previously infected with ΔUL56 became resistant to a lethal challenge with the wild-type SC16. The protective immunity induced by ΔUL56 was independent of IL-1, IL-33, and IL-36 signaling through IL-1RAP. Both skin and intramuscular ΔUL56 inoculation generated protective immunity against a lethal SC16 challenge. After 6 months, female mice remained resistant to infection, while male mice exhibited signs of declining protection. Our data demonstrate that UL56 is important for the ability of HSV-1 to spread within the infected host and that a ∆UL56 strain elicits an effective immune response against HSV-1 despite this loss of virulence. These findings may guide further HSV-1 vaccine development.

An Immunomodulator-Boosted Lactococcus Lactis Platform For Enhanced In Situ Tumor Vaccine.

In situ vaccination is an attractive type of cancer immunotherapy, and methods of persistently dispersing immune agonists throughout the entire tumor are crucial for maximizing their therapeutic efficacy. Based on the probiotics usually used for dietary supplements, an immunomodulator-boosted Lactococcus lactis (IBL) strategy is developed to enhance the effectiveness of in situ vaccination with the immunomodulators. The intratumoral delivery of OX40 agonist and resiquimod-modified Lactococcus lactis (OR@Lac) facilitates local retention and persistent dispersion of immunomodulators, and dramatically modulates the key components of anti-tumor immune response. This novel vaccine activated dendritic cells and cytotoxic T lymphocytes in the tumor and tumor-draining lymph nodes, and ultimately significantly inhibited tumor growth and prolonged the survival rate of tumor-bearing mice. The combination of OR@Lac and ibrutinib, a myeloid-derived suppressor cell inhibitor, significantly alleviated or even completely inhibited tumor growth in tumor-bearing mice. In conclusion, IBL is a promising in situ tumor vaccine approach for clinical application and provides an inspiration for the delivery of other drugs.

Tumor Neoepitope-Based Vaccines: A Scoping Review on Current Predictive Computational Strategies.

Therapeutic cancer vaccines have been considered in recent decades as important immunotherapeutic strategies capable of leading to tumor regression. In the development of these vaccines, the identification of neoepitopes plays a critical role, and different computational methods have been proposed and employed to direct and accelerate this process. In this context, this review identified and systematically analyzed the most recent studies published in the literature on the computational prediction of epitopes for the development of therapeutic vaccines, outlining critical steps, along with the associated program's strengths and limitations. A scoping review was conducted following the PRISMA extension (PRISMA-ScR). Searches were performed in databases (Scopus, PubMed, Web of Science, Science Direct) using the keywords: neoepitope, epitope, vaccine, prediction, algorithm, cancer, and tumor. Forty-nine articles published from 2012 to 2024 were synthesized and analyzed. Most of the identified studies focus on the prediction of epitopes with an affinity for MHC I molecules in solid tumors, such as lung carcinoma. Predicting epitopes with class II MHC affinity has been relatively underexplored. Besides neoepitope prediction from high-throughput sequencing data, additional steps were identified, such as the prioritization of neoepitopes and validation. Mutect2 is the most used tool for variant calling, while NetMHCpan is favored for neoepitope prediction. Artificial/convolutional neural networks are the preferred methods for neoepitope prediction. For prioritizing immunogenic epitopes, the random forest algorithm is the most used for classification. The performance values related to the computational models for the prediction and prioritization of neoepitopes are high; however, a large part of the studies still use microbiome databases for training. The in vitro/in vivo validations of the predicted neoepitopes were verified in 55% of the analyzed studies. Clinical trials that led to successful tumor remission were identified, highlighting that this immunotherapeutic approach can benefit these patients. Integrating high-throughput sequencing, sophisticated bioinformatics tools, and rigorous validation methods through in vitro/in vivo assays as well as clinical trials, the tumor neoepitope-based vaccine approach holds promise for developing personalized therapeutic vaccines that target specific tumor cancers.

Cytomegalovirus vaccine vector-induced effector memory CD4 + T cells protect cynomolgus macaques from lethal aerosolized heterologous avian influenza challenge

An influenza vaccine approach that overcomes the problem of viral sequence diversity and provides long-lived heterosubtypic protection is urgently needed to protect against pandemic influenza viruses. Here, to determine if lung-resident effector memory T cells induced by cytomegalovirus (CMV)-vectored vaccines expressing conserved internal influenza antigens could protect against lethal influenza challenge, we immunize Mauritian cynomolgus macaques (MCM) with cynomolgus CMV (CyCMV) vaccines expressing H1N1 1918 influenza M1, NP, and PB1 antigens (CyCMV/Flu), and challenge with heterologous, aerosolized avian H5N1 influenza. All six unvaccinated MCM died by seven days post infection with acute respiratory distress, while 54.5% (6/11) CyCMV/Flu-vaccinated MCM survived. Survival correlates with the magnitude of lung-resident influenza-specific CD4 + T cells prior to challenge. These data demonstrate that CD4 + T cells targeting conserved internal influenza proteins can protect against highly pathogenic heterologous influenza challenge and support further exploration of effector memory T cell-based vaccines for universal influenza vaccine development.

Identification and structural characterization of a mutant KRAS-G12V specific TCR restricted by HLA-A3.

Mutations in KRAS are some of the most common across multiple cancer types and are thus attractive targets for therapy. Recent studies demonstrated that mutant KRAS generates immunogenic neoantigens that are targetable by adoptive T-cell therapy in metastatic diseases. To expand mutant KRAS-specific immunotherapies, it is critical to identify additional HLA-I allotypes that can present KRAS neoantigens and their cognate T-cell receptors (TCR). Here, we identified a murine TCR specific to a KRAS-G12V neoantigen (7VVVGAVGVGK16) using a vaccination approach with transgenic mice expressing HLA-A*03:01 (HLA-A3). This TCR demonstrated exquisite specificity for mutant G12V and not WT KRAS peptides. To investigate the molecular basis for neoantigen recognition by this TCR, we determined its structure in complex with HLA-A3(G12V). G12V-TCR CDR3β and CDR1β formed a hydrophobic pocket to interact with p6 Val of the G12V but not the WT KRAS peptide. To improve the tumor sensitivity of this TCR, we designed rational substitutions to improve TCR:HLA-A3 contacts. Two substitutions exhibited modest improvements in TCR binding avidity to HLA-A3 (G12V) but did not sufficiently improve T-cell sensitivity for further clinical development. Our study provides mechanistic insight into how TCRs detect neoantigens and reveals the challenges in targeting KRAS-G12V mutations.

SARS-CoV-2 Vaccines: The Advantage of Mucosal Vaccine Delivery and Local Immunity.

Immunity against respiratory pathogens is often short-term, and, consequently, there is an unmet need for the effective prevention of such infections. One such infectious disease is coronavirus disease 19 (COVID-19), which is caused by the novel Beta coronavirus SARS-CoV-2 that emerged around the end of 2019. The World Health Organization declared the illness a pandemic on 11 March 2020, and since then it has killed or sickened millions of people globally. The development of COVID-19 systemic vaccines, which impressively led to a significant reduction in disease severity, hospitalization, and mortality, contained the pandemic's expansion. However, these vaccines have not been able to stop the virus from spreading because of the restricted development of mucosal immunity. As a result, breakthrough infections have frequently occurred, and new strains of the virus have been emerging. Furthermore, SARS-CoV-2 will likely continue to circulate and, like the influenza virus, co-exist with humans. The upper respiratory tract and nasal cavity are the primary sites of SARS-CoV-2 infection and, thus, a mucosal/nasal vaccination to induce a mucosal response and stop the virus' transmission is warranted. In this review, we present the status of the systemic vaccines, both the approved mucosal vaccines and those under evaluation in clinical trials. Furthermore, we present our approach of a B-cell peptide-based vaccination applied by a prime-boost schedule to elicit both systemic and mucosal immunity.

Optimal approaches for COVID-19 control: the use of vaccines and lockdowns across societal groups.

By March 2023, the COVID-19 illness had caused over 6.8 million deaths globally. Countries restricted disease spread through non-pharmaceutical interventions (NPIs; e.g. social distancing). More severe "lockdowns" were also required to manage disease spread. Although lockdowns effectively reduce virus transmission, they substantially disrupt economies and individual well-being. Fortunately, the availability of vaccines provides alternative approaches to manage disease spread. Yet, vaccination programs take several months to implement fully, require further time for individuals to develop immunity following inoculation, may not have complete coverage and/or may be imperfectly efficacious against the virus. Given these aspects of a vaccination programme, it is important to understand how NPIs (such as lockdowns) can be used in conjunction with vaccination to achieve public health goals. We use mathematical methods to, investigate optimal approaches for vaccination under varying lockdown lengths and/or severities to prevent COVID-19-related deaths exceeding critical thresholds. We find that increases in vaccination rate cause a disproportionate decrease in the length and severity lockdowns to keep mortality levels below a critical threshold. With vaccination, severe lockdowns can further reduce infections by up to 89%. Notably, we include simple demographics, modelling three groups: vulnerable, front-line workers, and non-vulnerable. We investigate the sequence of vaccination. One counter-intuitive finding is that even though the vulnerable group is high risk, demographically, this is a small group and critically, per person, vaccination therefore occurs more slowly. Hence vaccinating this group first achieves limited gains in overall disease control. Importantly, we conclude that improved disease control may be best achieved by vaccinating the non-vulnerable group coupled with longer and/or more severe NPIs.