Broad-spectrum pan-genus and pan-family virus vaccines.

Although the development and clinical application of SARS-CoV-2 vaccines during the COVID-19 pandemic demonstrated unprecedented vaccine success in a short time frame, it also revealed a limitation of current vaccines in their inability to provide broad-spectrum or universal protection against emerging variants. Broad-spectrum vaccines, therefore, remain a dream and challenge for vaccinology. This review will focus on current and future efforts in developing universal vaccines targeting different viruses at the genus and/or family levels, with a special focus on henipaviruses, influenza viruses, and coronaviruses. It is evident that strategies for developing broad-spectrum vaccines will be virus-genus or family specific, and it is almost impossible to adopt a universal approach for different viruses. On the other hand, efforts in developing broad-spectrum neutralizing monoclonal antibodies have been more successful and it is worth considering broad-spectrum antibody-mediated immunization, or "universal antibody vaccine," as an alternative approach for early intervention for future disease X outbreaks.

Potential of conserved antigenic sites in development of universal SARS-like coronavirus vaccines.

Given pandemic risks of zoonotic SARS-CoV-2 variants and other SARS-like coronaviruses in the future, it is valuable to perform studies on conserved antigenic sites to design universal SARS-like coronavirus vaccines. By using antibodies obtained from convalescent COVID-19 patients, we succeeded in functional comparison of conserved antigenic sites at multiple aspects with each other, and even with SARS-CoV-2 unique antigenic sites, which promotes the cognition of process of humoral immune response to the conserved antigenic sites. The conserved antigenic sites between SARS-CoV-2 and SARS-CoV can effectively induce affinity maturation of cross-binding antibodies, finally resulting in broadly neutralizing antibodies against multiple variants of concern, which provides an important basis for universal vaccine design, however they are subdominant, putatively due to their lower accessibility relative to SARS-CoV-2 unique antigenic sites. Furthermore, we preliminarily design RBDs to improve the immunogenicity of these conserved antigenic sites. Our study focusing on conserved antigenic sites provides insights for promoting the development of universal SARS-like coronavirus vaccines, thereby enhancing our pandemic preparedness.

COVID19-Far from Over: Call for Urgent Novel and Advanced Measures

The COVID19 pandemic that started in late 2019 has already killed millions people, it is yet far from over and the road to the COVID-free world is much tougher than we all imagined;however, it ends at a vaccine functional against all coronaviruses. In this article, we try to present the aetiology behind evolution of superior pathogenicity of SARS-CoV-2 and point out fundamen-tal and highly hazardous loopholes in the current vaccination regimens and propose new vaccination strategies. We also suggest societal and personal level management that are necessary to en-sure prevention and better recovery outcomes until the arrival of the vaccine. In turn, we apprise the physician for long-term and stringent management of certain chronic diseases, avoiding pre-scribing certain drugs and suggesting physical exercises and diets that are fortified with specific mi-cronutrients.Copyright © 2022 Bentham Science Publishers.

Inframarginal externalities: COVID-19, vaccines, and universal mandates.

COVID-19 vaccine mandates are in place or being debated across the world. Standard neoclassical economics argues that the marginal social benefit from vaccination exceeds the marginal private benefit; everyone vaccinated against a given infectious disease protects others by not transmitting the disease. Consequently, private levels of vaccination will be lower than the socially optimal levels due to free-riding, which requires mandates to overcome the problem. We argue that universal mandates based on free-riding are less compelling for COVID-19. We argue that because the virus can be transmitted even after receiving the vaccine, most of the benefits of the COVID-19 vaccine are internalized: vaccinated individuals are protected from the worst effects of the disease. Therefore, any positive externality may be inframarginal or policy irrelevant. Even when all the benefits are not internalized by the individual, the externalities mainly are local, mostly affecting family and closely associated individuals, requiring local institutional (private and civil society) arrangements to boost vaccine rates, even in a global pandemic. Economists and politicians must justify such universal vaccine mandates on some basis other than free-riding.

Vaccines against SARS-CoV-2 variants and future pandemics.

INTRODUCTION: Vaccination continues to be the most effective method for controlling COVID-19 infectious diseases. Nonetheless, SARS-CoV-2 variants continue to evolve and emerge, resulting in significant public concerns worldwide, even after more than 2 years since the COVID-19 pandemic. It is important to better understand how different COVID-19 vaccine platforms work, why SARS-CoV-2 variants continue to emerge, and what options for improving COVID-19 vaccines can be considered to fight against SARS-CoV-2 variants and future pandemics. AREA COVERED: Here, we reviewed the innate immune sensors in the recognition of SARS-CoV-2 virus, innate and adaptive immunity including neutralizing antibodies by different COVID-19 vaccines. Efficacy comparison of the several COVID-19 vaccine platforms approved for use in humans, concerns about SARS-CoV-2 variants and breakthrough infections, and the options for developing future COIVD-19 vaccines were also covered. EXPERT OPINION: Owing to the continuous emergence of novel pathogens and the reemergence of variants, safer and more effective new vaccines are needed. This review also aims to provide the knowledge basis for the development of next-generation COVID-19 and pan-coronavirus vaccines to provide cross-protection against new SARS-CoV-2 variants and future coronavirus pandemics.

Recent Progress in Recombinant Influenza Vaccine Development Toward Heterosubtypic Immune Response.

Flu, a viral infection caused by the influenza virus, is still a global public health concern with potential to cause seasonal epidemics and pandemics. Vaccination is considered the most effective protective strategy against the infection. However, given the high plasticity of the virus and the suboptimal immunogenicity of existing influenza vaccines, scientists are moving toward the development of universal vaccines. An important property of universal vaccines is their ability to induce heterosubtypic immunity, i.e., a wide immune response coverage toward different influenza subtypes. With the increasing number of studies and mounting evidence on the safety and efficacy of recombinant influenza vaccines (RIVs), they have been proposed as promising platforms for the development of universal vaccines. This review highlights the current progress and advances in the development of RIVs in the context of heterosubtypic immunity induction toward universal vaccine production. In particular, this review discussed existing knowledge on influenza and vaccine development, current hemagglutinin-based RIVs in the market and in the pipeline, other potential vaccine targets for RIVs (neuraminidase, matrix 1 and 2, nucleoprotein, polymerase acidic, and basic 1 and 2 antigens), and deantigenization process. This review also provided discussion points and future perspectives in looking at RIVs as potential universal vaccine candidates for influenza.

Strategy of developing nucleic acid-based universal monkeypox vaccine candidates.

Until May 2022, zoonotic infectious disease monkeypox (MPX) caused by the monkeypox virus (MPXV) was one of the forgotten viruses considered to be geographically limited in African countries even though few cases outside of Africa were identified. Central and West African countries are known to be endemic for MPXV. However, since the number of human MPX cases has rapidly increased outside of Africa the global interest in this virus has markedly grown. The majority of infected people with MPXV have never been vaccinated against smallpox virus. Noteworthily, the MPXV spreads fast in men who have sex with men (MSM). Preventive measures against MPXV are essential to be taken, indeed, vaccination is the key. Due to the antigenic similarities, the smallpox vaccine is efficient against MPXV. Nevertheless, there is no specific MPXV vaccine until now. Nucleic acid vaccines deserve special attention since the emergency approval of two messenger RNA (mRNA)-based coronavirus disease 2019 (COVID-19) vaccines in 2020. This milestone in vaccinology has opened a new platform for developing more mRNA- or DNA-based vaccines. Certainly, this type of vaccine has a number of advantages including time- and cost-effectiveness over conventional vaccines. The platform of nucleic acid-based vaccines gives humankind a huge opportunity. Ultimately, there is a strong need for developing a universal vaccine against MPXV. This review will shed the light on the strategies for developing nucleic acid vaccines against MPXV in a timely manner. Consequently, developing nucleic acid-based vaccines may alleviate the global threat against MPXV.

Promising strategy for developing mRNA-based universal influenza virus vaccine for human population, poultry, and pigs- focus on the bigger picture.

Since the first outbreak in the 19th century influenza virus has remained emergent owing to the huge pandemic potential. Only the pandemic of 1918 caused more deaths than any war in world history. Although two types of influenza- A (IAV) and B (IBV) cause epidemics annually, influenza A deserves more attention as its nature is much wilier. IAVs have a large animal reservoir and cause the infection manifestation not only in the human population but in poultry and domestic pigs as well. This many-sided characteristic of IAV along with the segmented genome gives rise to the antigenic drift and shift that allows evolving the new strains and new subtypes, respectively. As a result, the immune system of the body is unable to recognize them. Importantly, several highly pathogenic avian IAVs have already caused sporadic human infections with a high fatality rate (~60%). The current review discusses the promising strategy of using a potentially universal IAV mRNA vaccine based on conserved elements for humans, poultry, and pigs. This will better aid in averting the outbreaks in different susceptible species, thus, reduce the adverse impact on agriculture, and economics, and ultimately, prevent deadly pandemics in the human population.

Heterologous immunity induced by 1st generation COVID-19 vaccines and its role in developing a pan-coronavirus vaccine.

Severe acute respiratory syndrome virus-2 (SARS-CoV-2), the causative infectious agent of the COVID-19 pandemic, has led to multiple (4-6) waves of infections worldwide during the past two years. The development of vaccines against SARS-CoV-2 has led to successful mass immunizations worldwide, mitigating the worldwide mortality due the pandemic to a great extent. Yet the evolution of new variants highlights a need to develop a universal vaccine which can prevent infections from all virulent SARS-CoV-2. Most of the current first generation COVID-19 vaccines are based on the Spike protein from the original Wuhan-hu-1 virus strain. It is encouraging that they still protect from serious illnesses, hospitalizations and mortality against a number of mutated viral strains, to varying degrees. Understanding the mechanisms by which these vaccines provide heterologous protection against multiple highly mutated variants can reveal strategies to develop a universal vaccine. In addition, many unexposed individuals have been found to harbor T cells that are cross-reactive against SARS-CoV-2 antigens, with a possible protective role. In this review, we will discuss various aspects of natural or vaccine-induced heterologous (cross-reactive) adaptive immunity against SARS-CoV-2 and other coronaviruses, and their role in achieving the concept of a pan-coronavirus vaccine.

Severe acute respiratory syndrome coronavirus 2 variants-Possibility of universal vaccine design: A review

Both novel and conventional vaccination strategies have been implemented worldwide since the onset of coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite various medical advances in the treatment and prevention of the spread of this contagious disease, it remains a major public health threat with a high mortality rate. As several lethal SARS-CoV-2 variants continue to emerge, the development of several vaccines and medicines, each with certain advantages and disadvantages, is underway. Additionally, many modalities are at various stages of research and development or clinical trials. Here, we summarize emerging SARS-CoV-2 variants, including delta, omicron, and "stealth omicron," as well as available oral drugs for COVID-19. We also discuss possible antigen candidates other than the receptor-binding domain protein for the development of a universal COVID-19 vaccine. The present review will serve as a helpful resource for future vaccine and drug development to combat COVID-19.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Randomized, Double-Blind, Reference-Controlled, Phase 2a Study Evaluating the Immunogenicity and Safety of OVX836, A Nucleoprotein-Based Influenza Vaccine.

OVX836 is a recombinant protein-based vaccine targeting the highly conserved influenza nucleoprotein (NP), which aims to confer a broad-spectrum protection against influenza. In a Phase 1 study, OVX836, administered intramuscularly, has been found safe and immunogenic. The 90µg and 180µg dose levels were selected to be further evaluated in this randomized, monocenter, reference-controlled (Influvac Tetra™: quadrivalent seasonal influenza subunit vaccine), parallel group, double-blind, Phase 2a study in 300 healthy volunteers, aged 18-65 years, during the 2019/2020 flu season. Safety, influenza-like illness episodes (ILI; based on the Flu-PRO® questionnaire) and immunogenicity were assessed up to 180 days post-vaccination. OVX836 was safe and presented a reactogenicity profile similar to Influvac Tetra. It induced a significant increase in terms of NP-specific interferon-gamma (IFNγ) spot forming cells (SFCs), NP-specific CD4+ T-cells (essentially polyfunctional cells) and anti-NP IgG responses. OVX836 was superior to Influvac Tetra for all immunological parameters related to NP, and the 180µg dose was significantly superior to the 90µg dose for SFCs and CD4+ T-cells expressing IFNγ. Both the CD4+ T-cell and the anti-NP IgG responses persisted up to Day 180. An efficacy signal was observed with OVX836 at 180µg through reduction of ILI episodes occurring during the flu season as of 14 days post-vaccination. In conclusion, these results encourage further clinical evaluation of OVX836 in order to confirm the signal of efficacy on ILIs and/or laboratory-confirmed influenza cases. NCT04192500 (https://clinicaltrials.gov/ct2/show/study/NCT04192500).

Message in a bottle: mRNA vaccination for influenza.

Current influenza vaccines, while being the best method of managing viral outbreaks, have several major drawbacks that prevent them from being wholly-effective. They need to be updated regularly and require extensive resources to develop. When considering alternatives, the recent deployment of mRNA vaccines for SARS-CoV-2 has created a unique opportunity to evaluate a new platform for seasonal and pandemic influenza vaccines. The mRNA format has previously been examined for application to influenza and promising data suggest it may be a viable format for next-generation influenza vaccines. Here, we discuss the prospect of shifting global influenza vaccination efforts to an mRNA-based system that might allow better control over the product and immune responses and could aid in the development of a universal vaccine.

A biepitope, adjuvant-free, self-assembled influenza nanovaccine provides cross-protection against H3N2 and H1N1 viruses in mice.

Currently, the incorporation of multiple epitopes into vaccines is more desirable than the incorporation of a single antigen for universal influenza vaccine development. However, epitopes induce poor immune responses. Although the use of adjuvants can overcome this obstacle, it may raise new problems. Effective antigen delivery vehicles that can function as both antigen carriers and intrinsic adjuvants are highly desired for vaccine development. Here, we report a biepitope nanovaccine that provides complete protection in mice against H3N2 virus as well as partial protection against H1N1 virus. This vaccine (3MCD-f) consists of two conserved epitopes (matrix protein 2 ectodomain (M2e) and CDhelix), and these epitopes were presented on the surface of ferritin in a sequential tandem format. Subcutaneous immunization with 3MCD-f in the absence of adjuvant induces robust humoral and cellular immune responses. These results provide a proof of concept for the 3MCD-f nanovaccine that might be an ideal candidate for future influenza pandemics.

Broad and durable antibody response after vaccination with inactivated SARS-CoV-2 in individuals with a history of 2003 SARS-CoV infection.

In vaccinees who were infected with SARS-CoV in 2003, we observed greater antibody responses against spike and nucleoprotein of both SARS-CoV-2 and SARS-CoV after a single dosage of inactivated SARS-CoV-2 vaccine. After receiving the second vaccination, antibodies against RBD of SARS-CoV-2 Wuhan, Beta, Delta, and recently emerged Omicron are significantly higher in SARS-CoV experienced vaccinees than in SARS-CoV naïve vaccinees. Neutralizing activities measured by authentic viruses and pseudoviruses of SARS-CoV, SARS-CoV-2 Wuhan, Beta, and Delta are greater in SARS-CoV experienced vaccinees. In contrast, only weak neutralizing activities against SARS-CoV-2 and variants were detected in SARS-CoV naïve vaccinees. By 6 months after the second vaccination, neutralizing activities were maintained at a relatively higher level in SARS-CoV experienced vaccinees but were undetectable in SARS-CoV naïve vaccinees. These findings suggested a great possibility of developing a universal vaccine by heterologous vaccination using spike antigens from different SARS-related coronaviruses.

Designing AbhiSCoVac - A single potential vaccine for all 'corona culprits': Immunoinformatics and immune simulation approaches.

The coronaviridae family has generated highly virulent viruses, including the ones responsible for three major pandemics in last two decades with SARS in 2002, MERS outbreak in 2012 and the current nCOVID19 crisis that has turned the world breadthless. Future outbreaks are also a plausible threat to mankind. As computational biologists, we are committed to address the need for a universal vaccine that can deter all these pathogenic viruses in a single shot. Notably, the spike proteins present in all these viruses function as credible PAMPs that are majorly sensed by human TLR4 receptors. Our study aims to recognize the amino acid sequence(s) of the viral spike proteins that are precisely responsible for interaction with human TLR4 and to screen the immunogenic epitopes present in them to develop a multi-epitope multi-target chimeric vaccine against the coronaviruses. Molecular design of the constructed vaccine peptide is qualified in silico; additionally, molecular docking and molecular dynamics simulation studies collectively reveal strong and stable interactions of the vaccine construct with TLRs and MHC receptors. In silico cloning is performed for proficient expression in bacterial systems. In silico immune simulation of the vaccine indicates highly immunogenic nature of the vaccine construct without any allergic response. The present biocomputational study hereby innovates a vaccine candidate - AbhiSCoVac hypothesized as a potent remedy to combat all the virulent forms of coronaviruses.

Targeting Antigens for Universal Influenza Vaccine Development.

Traditional influenza vaccines generate strain-specific antibodies which cannot provide protection against divergent influenza virus strains. Further, due to frequent antigenic shifts and drift of influenza viruses, annual reformulation and revaccination are required in order to match circulating strains. Thus, the development of a universal influenza vaccine (UIV) is critical for long-term protection against all seasonal influenza virus strains, as well as to provide protection against a potential pandemic virus. One of the most important strategies in the development of UIVs is the selection of optimal targeting antigens to generate broadly cross-reactive neutralizing antibodies or cross-reactive T cell responses against divergent influenza virus strains. However, each type of target antigen for UIVs has advantages and limitations for the generation of sufficient immune responses against divergent influenza viruses. Herein, we review current strategies and perspectives regarding the use of antigens, including hemagglutinin, neuraminidase, matrix proteins, and internal proteins, for universal influenza vaccine development.

One step closer to influenza vaccine inclusiveness.

Flu virus infection is a common cause of acute respiratory illness, with the major incidence in pediatric age, high morbidity, and mortality. The flu vaccine is recommended for all people aged ≥6 months, unless specific contraindications are present. Younger and older age, pregnancy, chronic diseases like asthma, and immunodeficiency are risk factors for severe complications following flu infection. Thus, these categories represent the target for flu vaccine strategies in most countries. Inactivated influenza vaccine (IIV), recombinant influenza vaccine (RIV) or live-attenuated influenza virus (LAIV) are currently available, with specific precautions and contraindications. We aim to resume the current indications for vaccines in the vulnerable populations to support flu vaccination inclusiveness, in anticipation of a "universal vaccine" strategy.

New Technologies for Influenza Vaccines.

Vaccine development has been hampered by the long lead times and the high cost required to reach the market. The 2020 pandemic, caused by a new coronavirus (SARS-CoV-2) that was first reported in late 2019, has seen unprecedented rapid activity to generate a vaccine, which belies the traditional vaccine development cycle. Critically, much of this progress has been leveraged off existing technologies, many of which had their beginnings in influenza vaccine development. This commentary outlines the most promising of the next generation of non-egg-based influenza vaccines including new manufacturing platforms, structure-based antigen design/computational biology, protein-based vaccines including recombinant technologies, nanoparticles, gene- and vector-based technologies, as well as an update on activities around a universal influenza vaccine.

Prepare for the Future: Dissecting the Spike to Seek Broadly Neutralizing Antibodies and Universal Vaccine for Pandemic Coronaviruses.

Learning from the lengthy fight against HIV-1, influenza, and Ebola virus infection, broadly neutralizing antibodies (bnAbs), directed at conserved regions of surface proteins crucial to virus entry (Env, hemagglutinin, and GP, respectively), are an essential resource for passive as well as active immunization. Rare in their emergence and antigen recognition mode, bnAbs are active toward a large set of different viral strains. Isolation, characterization and production of bnAbs lead to their possible use in passive immunotherapy and form the basis for an educated effort in the development of vaccines for universal coverage. SARS-CoV-2-specific antibodies targeting the spike receptor binding domain (RBD) may lead to antibody dependent enhancement (ADE) of infection, possibly hampering the field of vaccine development. This perspective points to the identification of conserved regions in the spike of SARS-CoV-2, SARS-CoV, and MERS-CoV through investigation, dissection and recombinant production of isolated moieties. These spike moieties should be capable of independent folding and allow the detection as well as the elicitation of bnAbs, thus setting the basis for an effective passive immunotherapy and the development of a universal vaccine against human epidemic coronaviruses (HCoVs). SARS, MERS and, most of all, COVID-19 demonstrate that humanity is the target of HCoV, preparedness for future hits is thus no longer an option.