Recent studies have reported the protective efficacy of both natural
and vaccine-induced
immunity against challenge with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in rhesus ...macaques. However, the importance of humoral and cellular immunity for protection against infection with SARS-CoV-2 remains to be determined. Here we show that the adoptive transfer of purified IgG from convalescent rhesus macaques (Macaca mulatta) protects naive recipient macaques against challenge with SARS-CoV-2 in a dose-dependent fashion. Depletion of CD8
T cells in convalescent macaques partially abrogated the protective efficacy of natural immunity against rechallenge with SARS-CoV-2, which suggests a role for cellular immunity in the context of waning or subprotective antibody titres. These data demonstrate that relatively low antibody titres are sufficient for protection against SARS-CoV-2 in rhesus macaques, and that cellular immune responses may contribute to protection if antibody responses are suboptimal. We also show that higher antibody titres are required for treatment of SARS-CoV-2 infection in macaques. These findings have implications for the development of SARS-CoV-2 vaccines and immune-based therapeutic agents.
IMPORTANCE: Pregnant women are at increased risk of morbidity and mortality from COVID-19 but have been excluded from the phase 3 COVID-19 vaccine trials. Data on vaccine safety and immunogenicity in ...these populations are therefore limited. OBJECTIVE: To evaluate the immunogenicity of COVID-19 messenger RNA (mRNA) vaccines in pregnant and lactating women, including against emerging SARS-CoV-2 variants of concern. DESIGN, SETTING, AND PARTICIPANTS: An exploratory, descriptive, prospective cohort study enrolled 103 women who received a COVID-19 vaccine from December 2020 through March 2021 and 28 women who had confirmed SARS-CoV-2 infection from April 2020 through March 2021 (the last follow-up date was March 26, 2021). This study enrolled 30 pregnant, 16 lactating, and 57 neither pregnant nor lactating women who received either the mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) COVID-19 vaccines and 22 pregnant and 6 nonpregnant unvaccinated women with SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES: SARS-CoV-2 receptor binding domain binding, neutralizing, and functional nonneutralizing antibody responses from pregnant, lactating, and nonpregnant women were assessed following vaccination. Spike-specific T-cell responses were evaluated using IFN-γ enzyme-linked immunospot and multiparameter intracellular cytokine–staining assays. Humoral and cellular immune responses were determined against the original SARS-CoV-2 USA-WA1/2020 strain as well as against the B.1.1.7 and B.1.351 variants. RESULTS: This study enrolled 103 women aged 18 to 45 years (66% non-Hispanic White) who received a COVID-19 mRNA vaccine. After the second vaccine dose, fever was reported in 4 pregnant women (14%; SD, 6%), 7 lactating women (44%; SD, 12%), and 27 nonpregnant women (52%; SD, 7%). Binding, neutralizing, and functional nonneutralizing antibody responses as well as CD4 and CD8 T-cell responses were present in pregnant, lactating, and nonpregnant women following vaccination. Binding and neutralizing antibodies were also observed in infant cord blood and breast milk. Binding and neutralizing antibody titers against the SARS-CoV-2 B.1.1.7 and B.1.351 variants of concern were reduced, but T-cell responses were preserved against viral variants. CONCLUSION AND RELEVANCE: In this exploratory analysis of a convenience sample, receipt of a COVID-19 mRNA vaccine was immunogenic in pregnant women, and vaccine-elicited antibodies were transported to infant cord blood and breast milk. Pregnant and nonpregnant women who were vaccinated developed cross-reactive antibody responses and T-cell responses against SARS-CoV-2 variants of concern.
Many experimental therapies for autoimmune diseases, such as multiple sclerosis (MS), aim to bias T cells toward tolerogenic phenotypes without broad suppression. However, the link between local ...signal integration in lymph nodes (LNs) and the specificity of systemic tolerance is not well understood. We used intra-LN injection of polymer particles to study tolerance as a function of signals in the LN microenvironment. In a mouse MS model, intra-LN introduction of encapsulated myelin self-antigen and a regulatory signal (rapamycin) permanently reversed paralysis after one treatment during peak disease. Therapeutic effects were myelin specific, required antigen encapsulation, and were less potent without rapamycin. This efficacy was accompanied by local LN reorganization, reduced inflammation, systemic expansion of regulatory T cells, and reduced T cell infiltration to the CNS. Our findings suggest that local control over signaling in distinct LNs can promote cell types and functions that drive tolerance that is systemic but antigen specific.
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•A single intra-lymph node (i.LN.) particle dose reverses autoimmunity/paralysis in mice•Efficacy is dependent on delivery of encapsulated self-antigen to lymph nodes (LNs)•i.LN. delivery of particles reprograms local LN cell composition and function•Altered local function in LNs promotes systemic but antigen-specific tolerance
Tostanoski et al. show that a single direct injection of degradable particles into lymph nodes reverses paralysis in a mouse model of multiple sclerosis underpinned by myelin attack. This local reprogramming of the lymph node microenvironment toward regulatory function drives tolerance that is systemic but myelin specific.
Vaccines are critical tools for maintaining global health. Traditional vaccine technologies have been used across a wide range of bacterial and viral pathogens, yet there are a number of examples ...where they have not been successful, such as for persistent infections, rapidly evolving pathogens with high sequence variability, complex viral antigens, and emerging pathogens. Novel technologies such as nucleic acid and viral vector vaccines offer the potential to revolutionize vaccine development as they are well-suited to address existing technology limitations. In this review, we discuss the current state of RNA vaccines, recombinant adenovirus vector-based vaccines, and advances from biomaterials and engineering that address these important public health challenges.
Vaccines play a critical role in global health, and Gebre et al. review the current state of three vaccine development platforms (mRNA vaccines, vector-based vaccines, and materials science approaches to vaccination).
Materials that allow modular, defined assembly of immune signals could support a new generation of rationally designed vaccines that promote tunable immune responses. Toward this goal, we have ...developed the first polyelectrolyte multilayer (PEM) coatings built entirely from immune signals. These immune-PEMs (iPEMs) are self-assembled on gold nanoparticle templates through stepwise electrostatic interactions between peptide antigen and polyanionic toll-like receptor (TLR) agonists that serve as molecular adjuvants. iPEMs do not require solvents or mixing, offer direct control over the composition and loading of vaccine components, and can be coated on substrates at any scale. These films also do not require other structural components, eliminating the potentially confounding effects caused by the inherent immune-stimulatory characteristics of many synthetic polymers. iPEM loading on gold nanoparticle substrates is tunable, and cryoTEM reveals iPEM shells coated on gold cores. These nanoparticles are efficiently internalized by primary dendritic cells (DCs), resulting in activation, selective triggering of TLR signaling, and presentation of the antigens used to assemble iPEMs. In coculture, iPEMs drive antigen-specific T cell proliferation and effector cytokines but not cytokines associated with more generalized inflammation. Compared to mice treated with soluble antigen and adjuvant, iPEM immunization promotes high levels of antigen-specific CD8+ T cells in peripheral blood after 1 week. These enhancements result from increased DC activation and antigen presentation in draining lymph nodes. iPEM-immunized mice also exhibit a potent recall response after boosting, supporting the potential of iPEMs for designing well-defined vaccine coatings that provide high cargo density and eliminate synthetic film components.
The immune system is an awe-inspiring control structure that maintains a delicate and constantly changing balance between pro-immune functions that fight infection and cancer, regulatory or ...suppressive functions involved in immune tolerance, and homeostatic resting states. These activities are determined by integrating signals in space and time; thus, improving control over the densities, combinations, and durations with which immune signals are delivered is a central goal to better combat infectious disease, cancer, and autoimmunity. Self-assembly presents a unique opportunity to synthesize materials with well-defined compositions and controlled physical arrangement of molecular building blocks. This review highlights strategies exploiting these capabilities to improve the understanding of how precisely-displayed cues interact with immune cells and tissues. We present work centered on fundamental properties that regulate the nature and magnitude of immune response, highlight pre-clinical and clinical applications of self-assembled technologies in vaccines, cancer, and autoimmunity, and describe some of the key manufacturing and regulatory hurdles facing these areas.
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Despite the rapid creation of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccines, the precise correlates of immunity against severe Coronavirus Disease 2019 (COVID-19) are still ...unknown. Neutralizing antibodies represent a robust surrogate of protection in early Phase III studies, but vaccines provide protection prior to the evolution of neutralization, vaccines provide protection against variants that evade neutralization, and vaccines continue to provide protection against disease severity in the setting of waning neutralizing titers. Thus, in this study, using an Ad26.CoV2.S dose-down approach in nonhuman primates (NHPs), the role of neutralization, Fc effector function, and T-cell immunity were collectively probed against infection as well as against viral control. While dosing-down minimally impacted neutralizing and binding antibody titers, Fc receptor binding and functional antibody levels were induced in a highly dose-dependent manner. Neutralizing antibody and Fc receptor binding titers, but minimally T cells, were linked to the prevention of transmission. Conversely, Fc receptor binding/function and T cells were linked to antiviral control, with a minimal role for neutralization. These data point to dichotomous roles of neutralization and T-cell function in protection against transmission and disease severity and a continuous role for Fc effector function as a correlate of immunity key to halting and controlling SARS-CoV-2 and emerging variants.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant has proven to be highly transmissible and has outcompeted the Delta variant in many regions of the world. ...Early reports have also suggested that Omicron may result in less severe clinical disease in humans. Here, we show that Omicron is less pathogenic than prior SARS-CoV-2 variants in Syrian golden hamsters.
Hamsters were inoculated with either SARS-CoV-2 Omicron or other SARS-CoV-2 variants. Animals were followed for weight loss, and upper and lower respiratory tract tissues were assessed for viral loads and histopathology.
Infection of hamsters with the SARS-CoV-2 WA1/2020, Alpha, Beta, or Delta strains led to 4%–10% weight loss by day 4 and 10%–17% weight loss by day 6. In contrast, infection of hamsters with two different Omicron challenge stocks did not result in any detectable weight loss, even at high challenge doses. Omicron infection led to substantial viral replication in both the upper and lower respiratory tracts but demonstrated lower viral loads in lung parenchyma and reduced pulmonary pathology compared with WA1/2020 infection.
These data suggest that the SARS-CoV-2 Omicron variant may result in robust upper respiratory tract infection, but less severe lower respiratory tract clinical disease, compared with prior SARS-CoV-2 variants.
Funding for this study was provided by NIH grant CA260476, the Massachusetts Consortium for Pathogen Readiness, the Ragon Institute, and the Musk Foundation.
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•Omicron-infected Syrian golden hamsters did not lose weight•Omicron-infected hamsters had lower viral loads in lung than other variants•Omicron-infected hamsters showed less severe lung pathology than other variants
The SARS-CoV-2 Omicron variant has proven highly transmissible and has outcompeted the Delta variant in many regions of the world. In this study, investigators studied Omicron infection in Syrian golden hamsters. Although infection with prior SARS-CoV-2 variants led to substantial weight loss following infection in hamsters, infection with the Omicron variant did not result in any detectable weight loss, even at high challenge doses. Moreover, Omicron infection led to lower viral loads and reduced pathology in the lung compared with prior SARS-CoV-2 variants. These findings show that the SARS-CoV-2 Omicron variant led to less severe lower respiratory tract disease compared with prior SARS-CoV-2 variants in hamsters.
Syrian golden hamsters infected with the SARS-CoV-2 Omicron variant did not lose weight and showed less virus in the lung and reduced lung pathology compared with hamsters infected with prior SARS-CoV-2 variants. These observations are consistent with emerging human data suggesting that Omicron infection is less severe than infection with prior variants.
The Ad26.COV2.S vaccine
has demonstrated clinical efficacy against symptomatic COVID-19, including against the B.1.351 variant that is partially resistant to neutralizing antibodies
. However, the ...immunogenicity of this vaccine in humans against SARS-CoV-2 variants of concern remains unclear. Here we report humoral and cellular immune responses from 20 Ad26.COV2.S vaccinated individuals from the COV1001 phase I-IIa clinical trial
against the original SARS-CoV-2 strain WA1/2020 as well as against the B.1.1.7, CAL.20C, P.1 and B.1.351 variants of concern. Ad26.COV2.S induced median pseudovirus neutralizing antibody titres that were 5.0-fold and 3.3-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020 on day 71 after vaccination. Median binding antibody titres were 2.9-fold and 2.7-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020. Antibody-dependent cellular phagocytosis, complement deposition and natural killer cell activation responses were largely preserved against the B.1.351 variant. CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the WA1/2020, B.1.1.7, B.1.351, P.1 and CAL.20C variants. These data show that neutralizing antibody responses induced by Ad26.COV2.S were reduced against the B.1.351 and P.1 variants, but functional non-neutralizing antibody responses and T cell responses were largely preserved against SARS-CoV-2 variants. These findings have implications for vaccine protection against SARS-CoV-2 variants of concern.
Severe disease due to COVID-19 has declined dramatically as a result of widespread vaccination and natural immunity in the population. With the emergence of SARS-CoV-2 variants that largely escape ...vaccine-elicited neutralizing antibody responses, the efficacy of the original vaccines has waned and has required vaccine updating and boosting. Nevertheless, hospitalizations and deaths due to COVID-19 have remained low. In this review, we summarize current knowledge of immune responses that contribute to population immunity and the mechanisms how vaccines attenuate COVID-19 disease severity.
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