Broad Immunity Research Articles

A bivalent vaccine containing D614G and BA.1 spike trimer proteins or a BA.1 spike trimer protein booster shows broad neutralizing immunity.

The newly emerged severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) Omicron variant, sublineages BA.1 and BA.2, recently became the dominant variants of concern (VOCs) with significantly higher transmissibility than any other variant appeared and markedly greater resistance to neutralization antibodies and original ancestral WA1 spike-matched vaccine. Therefore, it is urgent to develop vaccines against VOCs like Omicron. Unlike the new booming messenger RNA (mRNA) vaccine, protein vaccines have been used for decades to protect people from various kinds of viral infections and have advantages with their inexpensive production protocols and their relative stability in comparison to themRNA vaccine. Here, we show that sera from BA.1 spike protein vaccinated mice mainly elicited neutralizing antibodies against BA.1 itself. However, a booster with BA.1 spike protein or a bivalent vaccine composed of D614G and BA.1 spike protein-induced not only potent neutralizing antibody response against D614G and BA.1 pseudovirus, but also against BA.2, other four SARS-CoV-2 VOCs (Alpha, Beta, Gamma, and Delta) and SARS-CoV-2-related coronaviruses (pangolin CoV GD-1 and bat CoV RsSHC014). The two recombinant spike protein vaccines method described here lay a foundation for future vaccine development for broad protection against pan-sarbecovirus.

Structural basis for broad anti-phage immunity by DISARM

In the evolutionary arms race against phage, bacteria have assembled a diverse arsenal of antiviral immune strategies. While the recently discovered DISARM (Defense Island System Associated with Restriction-Modification) systems can provide protection against a wide range of phage, the molecular mechanisms that underpin broad antiviral targeting but avoiding autoimmunity remain enigmatic. Here, we report cryo-EM structures of the core DISARM complex, DrmAB, both alone and in complex with an unmethylated phage DNA mimetic. These structures reveal that DrmAB core complex is autoinhibited by a trigger loop (TL) within DrmA and binding to DNA substrates containing a 5′ overhang dislodges the TL, initiating a long-range structural rearrangement for DrmAB activation. Together with structure-guided in vivo studies, our work provides insights into the mechanism of phage DNA recognition and specific activation of this widespread antiviral defense system.

Intranasal administration of a recombinant RBD vaccine induces long-term immunity against Omicron-included SARS-CoV-2 variants

The outbreak of coronavirus disease 2019 (COVID-19) has posed great threats to global health and economy. Several effective vaccines are available now, but additional booster immunization is required to retain or increase the immune responses owing to waning immunity and the emergency of new variant strains. The deficiency of intramuscularly delivered vaccines to induce mucosal immunity urged the development of mucosal vaccines. Here, we developed an adjuvanted intranasal RBD vaccine and monitored its long-term immunogenicity against both wild-type and mutant strains of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), including Omicron variants, in mice. Three-dose intranasal immunization with this vaccine induced and maintained high levels of neutralizing IgG antibodies in the sera for at least 1 year. Strong mucosal immunity was also provoked, including mucosal secretory IgA and lung-resident memory T cells (TRM). We also demonstrated that the long-term persistence of lung TRM cells is a consequence of local T-cell proliferation, rather than T-cell migration from lymph nodes. Our data suggested that the adjuvanted intranasal RBD vaccine is a promising vaccine candidate to establish robust, long-lasting, and broad protective immunity against SARS-CoV-2 both systemically and locally.

Broad humoral and cellular immunity elicited by one-dose mRNA vaccination 18 months after SARS-CoV-2 infection

BackgroundPractical guidance is needed regarding the vaccination of coronavirus disease 2019 (COVID-19) convalescent individuals in resource-limited countries. It includes the number of vaccine doses that should be given to unvaccinated patients who experienced COVID-19 early in the pandemic.MethodsWe recruited COVID-19 convalescent individuals who received one or two doses of an mRNA vaccine within 6 or around 18 months after a diagnosis of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Their samples were assessed for IgG-binding or neutralizing activity and cell-mediated immune responses against SARS-CoV-2 wild-type and variants of concern.ResultsA total of 43 COVID-19 convalescent individuals were analyzed in the present study. The results showed that humoral and cellular immune responses against SARS-CoV-2 wild-type and variants of concern, including the Omicron variant, were comparable among patients vaccinated within 6 versus around 18 months. A second dose of vaccine did not significantly increase immune responses.ConclusionOne dose of mRNA vaccine should be considered sufficient to elicit a broad immune response even around 18 months after a COVID-19 diagnosis.

Booster COVID-19 vaccination against the SARS-CoV-2 Omicron variant: A systematic review

ABSTRACT There is a wealth of data suggesting that the effectiveness of existing vaccines against the Omicron variant, the most mutated SARS-CoV-2 variant to date, has been substantially reduced if only primary vaccination is administered. Therefore, the effectiveness of booster vaccination against the Omicron variant has become a topic of current interest. We conducted a comprehensive search in PubMed, Embase, and the Cochrane Library to collect various pseudovirus neutralization tests or live virus neutralization tests for the Omicron variant, with serum specimens from booster vaccinees. We extracted neutralization titers for the Omicron variant, the original strain, and the other variants before and after booster vaccination, and then manually calculated the fold increase or decrease in neutralization titers for the Omicron variant relative to the other variants, and the fold increase in neutralization titers for the Omicron variant after booster vaccination compared with that before booster vaccination. In the two-dose vaccination regimen, the neutralization titers against the Omicron variant decreased substantially compared to the original strain and other variants. However, after booster vaccination, both homologous and heterologous booster vaccination, the neutralization of serum antibodies against the Omicron variant was significantly improved, although still lower than that of the original strain and other variants. The booster vaccination program based on existing vaccines can produce broad but incomplete immunity against the Omicron variant.

Superiorly Broad Natural Immunity to Covid Infection Can Potentially Provide Longer Lasting Protection against Immune Evasion by Emerging Variants from Alpha to Omicron and Possibly Beyond to Omega

COVID has become one of the deadliest obligate intracellular pathogens in over 100 years. COVID pandemic’s devastation causing to date 6.05+ million global deaths from over 460 million confirmed positive infections globally in just 2 years and close to 964,000+ US deaths out of 79.5 million confirmed positive cases in the US, continues with no sign of eradication of the virus. Antigenic variation is a predominant way of microorganisms causing human diseases to evade innate and acquired immunity. A major reason for that is COVID’s ability to evade human innate and acquired immune defenses by antigenic variation and to breach the weaker immune defenses of those among us who could not mount a timely and effective immune response to sustain ferocious attack on lungs and survive with great difficulty or succumb to an inability to breathe. While it is globally observed by Physician scientists that the OMICRON variant is highly transmissible but causes only MILD symptoms, because it is present only in the upper respiratory tract. A more virulent variant having a similar ability to spread fast could be catastrophic. How can immune evasion by COVID and its emerging variants be circumvented with better vaccines and treatments? It is high time to develop second generation of vaccines with broader protection that more closely simulates natural infection and viral entry inhibitors, eg. enveloped virus neutralizing compounds (EVNCs) that have proven broad spectrum neutralization of pandemic Influenza viruses like H5N1 or SARS-CoV-1, could prove effective against emerged and rapidly emerging strains of COVID like Omicron. A lab. Report a year after prior severe COVID infections but without any vaccine or booster dose clearly suggests that natural immunity acquired during infection is long lasting and should be meaningfully recognized by CDC and other agencies as, at least equivalent by immunization with vaccines against the emerging variants mutating periodically due to genetic variation and viral evasion.

Chinese digital platforms in Australia: From market and politics to governance

Through the lens of platform governance, this paper examines the market, politics, and governance of made-in-China digital platforms in Australia, with a focus on WeChat and TikTok. It investigates how formal and informal arrangements are intertwined in the governance regimes and market strategies of these Chinese digital platforms when trying to navigate the turbulent waters of intensified Sino-Australia relations and a global trend towards increased government intervention in platform governance. The two made-in-China platforms represent two different models in platform governance adopted by Tencent and ByteDance: one conditioned by the Chinese ‘strict liability’ model and the other leaning toward the Western ‘broad immunity’ model. The Australian case illustrates the strife, success and politics of outbound Chinese digital platforms in a Western liberal democracy. It also highlights the dilemma, conundrum, and possible breakthrough in platform governance on a splintered and yet increasingly interconnected social media space.

Cocktail party: Low-dose antibody combinations deliver pan-ebolavirus protection

Recent outbreaks of Ebola have brought to the forefront the need for focused therapeutic treatments. In this issue of Cell, Milligan and colleagues build on previous studies of antibody treatments for Ebola virus disease, uncovering broad synergistic protective immunity when administered in combination (as antibody cocktails).

Predicting COVID-19 booster vaccine intentions.

Achieving broad immunity through vaccination is a cornerstone strategy for long‐term management of COVID‐19 infections, particularly the prevention of serious cases and hospitalizations. Evidence that vaccine‐induced immunity wanes over time points to the need for COVID‐19 booster vaccines, and maximum compliance is required to maintain population‐level immunity. Little is known of the correlates of intentions to receive booster vaccines among previously vaccinated individuals. The present study applied an integrated model to examine effects of beliefs from multiple social cognition theories alongside sets of generalized, stable beliefs on individuals' booster vaccine intentions. US residents (N = 479) recruited from an online survey panel completed measures of social cognition constructs (attitude, subjective norms, perceived behavioral control, and risk perceptions), generalized beliefs (vaccine hesitancy, political orientation, and free will beliefs), and COVID‐19 vaccine intentions. Social cognition constructs were related to booster vaccine intentions, with attitude and subjective norms exhibiting the largest effects. Effects of vaccine hesitancy, political orientation, and free will beliefs on intentions were mediated by the social cognition constructs, and only vaccine hesitancy had a small residual effect on intentions. Findings provide preliminary evidence that contributes to an evidence base of potential targets for intervention messages aimed at promoting booster vaccine intentions.

Plant SYP12 syntaxins mediate an evolutionarily conserved general immunity to filamentous pathogens.

Filamentous fungal and oomycete plant pathogens that invade by direct penetration through the leaf epidermal cell wall cause devastating plant diseases. Plant preinvasive immunity toward nonadapted filamentous pathogens is highly effective and durable. Pre- and postinvasive immunity correlates with the formation of evolutionarily conserved and cell-autonomous cell wall structures, named papillae and encasements, respectively. Yet, it is still unresolved how papillae/encasements are formed and whether these defense structures prevent pathogen ingress. Here, we show that in Arabidopsis the two closely related members of the SYP12 clade of syntaxins (PEN1 and SYP122) are indispensable for the formation of papillae and encasements. Moreover, loss-of-function mutants were hampered in preinvasive immunity toward a range of phylogenetically distant nonadapted filamentous pathogens, underlining the versatility and efficacy of this defense. Complementation studies using SYP12s from the early diverging land plant, Marchantia polymorpha, showed that the SYP12 clade immunity function has survived 470 million years of independent evolution. These results suggest that ancestral land plants evolved the SYP12 clade to provide a broad and durable preinvasive immunity to facilitate their life on land and pave the way to a better understanding of how adapted pathogens overcome this ubiquitous plant defense strategy.

SARS-CoV-2 breakthrough infections elicit potent, broad, and durable neutralizing antibody responses

Although infections among vaccinated individuals lead to milder COVID-19 symptoms relative to those in unvaccinated subjects, the specificity and durability of antibody responses elicited by breakthrough cases remain unknown. Here, we demonstrate that breakthrough infections induce serum-binding and -neutralizing antibody responses that are markedly more potent, durable, and resilient to spike mutations observed in variants than those in subjects who received only 2 doses of vaccine. However, we show that breakthrough cases, subjects who were vaccinated after infection, and individuals vaccinated three times have serum-neutralizing activity of comparable magnitude and breadth, indicating that an increased number of exposures to SARS-CoV-2 antigen(s) enhance the quality of antibody responses. Neutralization of SARS-CoV was moderate, however, underscoring the importance of developing vaccines eliciting broad sarbecovirus immunity for pandemic preparedness.

Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry.

Understanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures against SARS-CoV-2 variants and future zoonotic sarbecoviruses. We describe the isolation and characterization of a human monoclonal antibody, designated S2K146, that broadly neutralizes viruses belonging to SARS-CoV- and SARS-CoV-2-related sarbecovirus clades which use ACE2 as an entry receptor. Structural and functional studies show that most of the virus residues that directly bind S2K146 are also involved in binding to ACE2. This allows the antibody to potently inhibit receptor attachment. S2K146 protects against SARS-CoV-2 Beta challenge in hamsters and viral passaging experiments reveal a high barrier for emergence of escape mutants, making it a good candidate for clinical development. The conserved ACE2-binding residues present a site of vulnerability that might be leveraged for developing vaccines eliciting broad sarbecovirus immunity.

Engineered Nanoparticulate Vaccines to Combat Recurring and Pandemic Influenza Threats.

Reoccurring seasonal flu epidemics and occasional pandemics are among the most severe threats to public health. Current seasonal influenza vaccines provide limited protection against drifted circulating strains and no protection against influenza pandemics. Next-generation influenza vaccines, designated as universal influenza vaccines, should be safe, affordable, and elicit long-lasting cross-protective influenza immunity. Nanotechnology plays a critical role in the development of such novel vaccines. Engineered nanoparticles can incorporate multiple advantageous properties into the same nanoparticulate platforms to improve vaccine potency and breadth. These immunological properties include virus-like biomimicry, high antigen-load, controlled antigen release, targeted delivery, and induction of innate signaling pathways. Many nanoparticle influenza vaccines have shown promising results in generating potent and broadly protective immune responses. This review will summarize the necessity and characteristics of next-generation influenza vaccines and the immunological correlates of broad influenza immunity and focus on how cutting-edge nanoparticle technology contributes to such vaccine development. The review will give new insights into the rational design of nanoparticle universal vaccines to combat influenza epidemics and pandemics.

The germinal centre B cell response to SARS-CoV-2.

The germinal centre (GC) response is critical for the generation of affinity-matured plasma cells and memory B cells capable of mediating long-term protective immunity. Understanding whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination elicits a GC response has profound implications for the capacity of responding B cells to contribute to protection against infection. However, direct assessment of the GC response in humans remains a major challenge. Here we summarize emerging evidence for the importance of the GC response in the establishment of durable and broad immunity against SARS-CoV-2 and discuss new approaches to modulate the GC response to better protect against newly emerging SARS-CoV-2 variants. We also discuss new findings showing that the GC B cell response persists in the draining lymph nodes for at least 6 months in some individuals following vaccination with SARS-CoV-2 mRNA-based vaccines.

Filling the Void? A Critical Analysis of Competition Regulation of Collective Bargaining Amongst Non-employees

The rise of the gig economy, and the expansion of self-employment more generally, have magnified pre-existing concerns about how to address the risk of exploitation of non-employees, including franchisees, freelance journalists and owner-driver transport workers, amongst others. In a bid to fill relevant regulatory gaps, and correct destructive power imbalances, many are turning their attention to the power and potential of collective bargaining. At the same time, there is growing appreciation of how competition prohibitions against price-fixing may curb workers’ capacity to organize for decent wages and working conditions. There has been much discussion and debate about the need to expand existing labour exemptions from competition law in order to allow gig workers, and other vulnerable categories of selfemployed workers, to engage in lawful collective bargaining. Rather than fixating on questions of misclassification, however, this article considers a novel proposal emanating from the sphere of competition regulation in Australia. After extensive consultation and prolonged Parliamentary debate, the Australian Competition and Consumer Commission (ACCC) has adopted a class exemption which provides a broad legal immunity to eligible small businesses, including self-employed workers, wishing to engage in collective bargaining. The ACCC’s Determination to extend collective bargaining rights to small businesses – with effect from 3 June 2021 – represents a highly progressive approach and one worthy of greater attention and deeper analysis. To assess the regulatory value of this unique approach, we draw upon the International Labour Organization (ILO) standards relating to collective bargaining and freedom of association. In doing so, we critically assess the extent to which the ACCC’s approach offers a potential solution to resolving the tension between labour law and competition law when it comes to the regulation of self-employed workers. Somewhat surprisingly, we find that the class exemption largely complies with relevant ILO principles, despite the fact that it does little in terms of actively promoting or encouraging effective collective bargaining. For example, in line with ILO conceptions of voluntariness, the class exemption places virtually no restrictions on the scope, level or subject matter of the bargaining. Ultimately, however, we argue that if collective bargaining is to have any chance of filling the regulatory void which exists between labour law and competition law, it is critical that basic structures and supports are in place to facilitate meaningful bargaining: where collective activity is supported by trade union autonomy and the right to engage in strikes in support of bargaining demands and concluded agreements. Mercosur, Socio-Labour Declaration, Argentina, Brazil, Uruguay, Paraguay, Venezuela, Regional Integration, Labour Rights, Regional Trade Blocs, Latin America, Global South

A two-adjuvant multiantigen candidate vaccine induces superior protective immune responses against SARS-CoV-2 challenge.

An ideal vaccine against SARS-CoV-2 is expected to elicit broad immunity to prevent viral infection and disease, with efficient viral clearance in the upper respiratory tract (URT). Here, the N protein and prefusion-full S protein (SFLmut) are combined with flagellin (KF) and cyclic GMP-AMP (cGAMP) to generate a candidate vaccine, and this vaccine elicits stronger systemic and mucosal humoral immunity than vaccines containing other forms of the S protein. Furthermore, the candidate vaccine administered via intranasal route can enhance local immune responses in the respiratory tract. Importantly, human ACE2 transgenic mice given the candidate vaccine are protected against lethal SARS-CoV-2 challenge, with superior protection in the URT compared with that in mice immunized with an inactivated vaccine. In summary, the developed vaccine can elicit a multifaceted immune response and induce robust viral clearance in the URT, which makes it a potential vaccine for preventing disease and infection of SARS-CoV-2.

A defective viral genome strategy elicits broad protective immunity against respiratory viruses

RNA viruses generate defective viral genomes (DVGs) that can interfere with replication of the parental wild-type virus. To examine their therapeutic potential, we created a DVG by deleting the capsid-coding region of poliovirus. Strikingly, intraperitoneal or intranasal administration of this genome, which we termed eTIP1, elicits an antiviral response, inhibits replication, and protects mice from several RNA viruses, including enteroviruses, influenza, and SARS-CoV-2. While eTIP1 replication following intranasal administration is limited to the nasal cavity, its antiviral action extends non-cell-autonomously to the lungs. eTIP1 broad-spectrum antiviral effects are mediated by both local and distal type I interferon responses. Importantly, while a single eTIP1 dose protects animals from SARS-CoV-2 infection, it also stimulates production of SARS-CoV-2 neutralizing antibodies that afford long-lasting protection from SARS-CoV-2 reinfection. Thus, eTIP1 is a safe and effective broad-spectrum antiviral generating short- and long-term protection against SARS-CoV-2 and other respiratory infections in animal models.

Synergism between CAR-T Cells and a Personalized Tumor Vaccine in Hematological Malignances

Synergism between CAR-T Cells and a Personalized Tumor Vaccine in Hematological Malignances

Fast and long-lasting immune response to S-trimer COVID-19 vaccine adjuvanted by PIKA

In the face of the emerging variants of SARS-CoV-2, there is an urgent need to develop a vaccine that can induce fast, effective, long-lasting and broad protective immunity against SARS-CoV-2. Here, we developed a trimeric SARS-CoV-2 S protein vaccine candidate adjuvanted by PIKA, which can induce robust cellular and humoral immune responses. The results showed a high level of neutralizing antibodies induced by the vaccine was maintained for at least 400 days. In the study of non-human primates, PIKA adjuvanted S-trimer induced high SARS-CoV-2 neutralization titers and protected from virus replication in the lung following SARS-CoV-2 challenge. In addition, the long-term neutralizing antibody response induced by S-trimer vaccine adjuvanted by PIKA could neutralize multiple SARS-CoV-2 variants and there is no obvious different among the SARS- CoV-2 variants of interest or concern, including B.1.351, B.1.1.7, P.1, B.1.617.1 and B.1.617.2 variants. These data support the utility of S-trimer protein adjuvanted by PIKA as a potential vaccine candidate against SARS-CoV-2 infection.

Inhibition of IRGM establishes a robust antiviral immune state to restrict pathogenic viruses.

The type I interferon (IFN) response is the major host arsenal against invading viruses. IRGM is a negative regulator of IFN responses under basal conditions. However, the role of human IRGM during viral infection has remained unclear. In this study, we show that IRGM expression is increased upon viral infection. IFN responses induced by viral PAMPs are negatively regulated by IRGM. Conversely, IRGM depletion results in a robust induction of key viral restriction factors including IFITMs, APOBECs, SAMHD1, tetherin, viperin, and HERC5/6. Additionally, antiviral processes such as MHC‐I antigen presentation and stress granule signaling are enhanced in IRGM‐deficient cells, indicating a robust cell‐intrinsic antiviral immune state. Consistently, IRGM‐depleted cells are resistant to the infection with seven viruses from five different families, including Togaviridae, Herpesviridae, Flaviviverdae, Rhabdoviridae, and Coronaviridae. Moreover, we show that Irgm1 knockout mice are highly resistant to chikungunya virus (CHIKV) infection. Altogether, our work highlights IRGM as a broad therapeutic target to promote defense against a large number of human viruses, including SARS‐CoV‐2, CHIKV, and Zika virus.