The new vaccines against SARS-CoV-2 are novel in terms of specificity, their wide dissemination across the global population and the inclusion of newly licensed mRNA platforms. We discuss here how the approved vaccines trigger innate immunity to promote durable immunological memory and consider the future implications of protecting populations with these vaccines. This Comment outlines how the recently licensed vaccines for COVID-19 activate innate immune mechanisms to promote immune memory to SARS-CoV-2. The authors also consider future challenges that could limit vaccine efficacy.

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COVID-19 vaccines: modes of immune activation and future challenges.

Adenoviral vectors are a safe and potently immunogenic vaccine delivery platform. Non-replicating Ad vectors possess several attributes which make them attractive vaccines for infectious disease, including their capacity for high titer growth, ease of manipulation, safety, and immunogenicity in clinical studies, as well as their compatibility with clinical manufacturing and thermo-stabilization procedures. In general, Ad vectors are immunogenic vaccines, which elicit robust transgene antigen-specific cellular (namely CD8+ T cells) and/or humoral immune responses. A large number of adenoviruses isolated from humans and non-human primates, which have low seroprevalence in humans, have been vectorized and tested as vaccines in animal models and humans. However, a distinct hierarchy of immunological potency has been identified between diverse Ad vectors, which unfortunately limits the potential use of many vectors which have otherwise desirable manufacturing characteristics. The precise mechanistic factors which underlie the profound disparities in immunogenicity are not clearly defined and are the subject of ongoing, detailed investigation. It has been suggested that a combination of factors contribute to the potent immunogenicity of particular Ad vectors, including the magnitude and duration of vaccine antigen expression following immunization. Furthermore, the excessive induction of Type I interferons by some Ad vectors has been suggested to impair transgene expression levels, dampening subsequent immune responses. Therefore, the induction of balanced, but not excessive stimulation of innate signaling is optimal. Entry factor binding or receptor usage of distinct Ad vectors can also affect their in vivo tropism following administration by different routes. The abundance and accessibility of innate immune cells and/or antigen-presenting cells at the site of injection contributes to early innate immune responses to Ad vaccination, affecting the outcome of the adaptive immune response. Although a significant amount of information exists regarding the tropism determinants of the common human adenovirus type-5 vector, very little is known about the receptor usage and tropism of rare species or non-human Ad vectors. Increased understanding of how different facets of the host response to Ad vectors contribute to their immunological potency will be essential for the development of optimized and customized Ad vaccine platforms for specific diseases.

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Factors Which Contribute to the Immunogenicity of Non-replicating Adenoviral Vectored Vaccines

SARS-CoV-2 vaccines: Lights and shadows.

Inaccuracies in prediction of circulating viral strain genotypes and the possibility of novel reassortants causing a pandemic outbreak necessitate the development of an anti-influenza vaccine with increased breadth of protection and potential for rapid production and deployment. The hemagglutinin (HA) stem is a promising target for universal influenza vaccine as stem-specific antibodies have the potential to be broadly cross-reactive towards different HA subtypes. Here, we report the design of a bacterially expressed polypeptide that mimics a H5 HA stem by protein minimization to focus the antibody response towards the HA stem. The HA mini-stem folds as a trimer mimicking the HA prefusion conformation. It is resistant to thermal/chemical stress, and it binds to conformation-specific, HA stem-directed broadly neutralizing antibodies with high affinity. Mice vaccinated with the group 1 HA mini-stems are protected from morbidity and mortality against lethal challenge by both group 1 (H5 and H1) and group 2 (H3) influenza viruses, the first report of cross-group protection. Passive transfer of immune serum demonstrates the protection is mediated by stem-specific antibodies. Furthermore, antibodies indudced by these HA stems have broad HA reactivity, yet they do not have antibody-dependent enhancement activity.

Stalking influenza by vaccination with pre-fusion headless HA mini-stem for broadly reactive antibodies

Coronavirus disease 2019 (COVID-19) pandemic continues to constitute a public health emergency of international concern. Multiple vaccine candidates for COVID-19, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have entered clinical trials. However, some evidence suggests that patients who have recovered from COVID-19 can be reinfected. For example, in China, two discharged COVID-19 patients who had recovered and fulfilled the discharge criteria for COVID-19 were retested positive to a reverse transcription polymerase chain reaction (RT-PCR) assay for the virus. This finding is critical and could hamper COVID-19 vaccine development. This review offers literature-based evidence of reinfection with SARS-CoV-2, provides explanation for the possibility of SARS-CoV-2 reinfection both from the agent and host points of view, and discusses its implication for COVID-19 vaccine development.

https://www.tandfonline.com/doi/pdf/10.1080/21645515.2020.1830683

SARS-CoV-2 reinfection and implications for vaccine development.

Introduction: Annual vaccination is one of the most efficient and cost-effective strategies to prevent and control influenza epidemics. Most of the currently available influenza vaccines are strong...

Vaccine approaches conferring cross-protection against influenza viruses.

https://www.mdpi.com/2076-393X/8/4/574/pdf

Adenoviral Vector-Based Vaccine Platforms for Developing the Next Generation of Influenza Vaccines.

The emergence of H5, H7, and H9 avian influenza virus subtypes in humans reveals their pandemic potential. Although human-to-human transmission has been limited, the genetic reassortment of the avian and human/porcine influenza viruses or mutations in some of the genes resulting in virus replication in the upper respiratory tract of humans could generate novel pandemic influenza viruses. Current vaccines do not provide cross protection against antigenically distinct strains of the H5, H7, and H9 influenza viruses. Therefore, newer vaccine approaches are needed to overcome these potential threats. We developed an egg-independent, adenovirus vector-based, multi-epitope (ME) vaccine approach using the relatively conserved immunogenic domains of the H5N1 influenza virus [M2 ectodomain (M2e), hemagglutinin (HA) fusion domain (HFD), T-cell epitope of nucleoprotein (TNP). and HA α-helix domain (HαD)]. Our ME vaccine induced humoral and cell-mediated immune responses and caused a significant reduction in the viral loads in the lungs of vaccinated mice that were challenged with antigenically distinct H5, H7, or H9 avian influenza viruses. These results suggest that our ME vaccine approach provided broad protection against the avian influenza viruses. Further improvement of this vaccine will lead to a pre-pandemic vaccine that may lower morbidity, hinder transmission, and prevent mortality in a pandemic situation before a strain-matched vaccine becomes available.

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Adenovirus vector-based multi-epitope vaccine provides partial protection against H5, H7, and H9 avian influenza viruses.

Longevity of adenovirus vector immunity in mice and its implications for vaccine efficacy

Various adenovirus (AdV) vector systems have proven to be lucrative options for gene delivery. They can serve as potential vaccine candidates for prevention of several common infectious diseases and hold the promise for gene therapy, especially for cancer. Several AdV vector-based therapies are currently at various stages of clinical trials worldwide, which make an immense interest of both the clinicians and researchers. Since these vectors are easy to manipulate, have broad tropism, and have the capability to yield high titers, this delivery system has a wide range of applications for different clinical settings. This chapter emphasizes on some of the current usages of AdV vectors and their production methods.

Ekramy E. Sayedahmed

Papers

Vaccine approaches conferring cross-protection against influenza viruses.

Adenoviral Vector-Based Vaccine Platforms for Developing the Next Generation of Influenza Vaccines.

Adenovirus vector-based multi-epitope vaccine provides partial protection against H5, H7, and H9 avian influenza viruses.

Longevity of adenovirus vector immunity in mice and its implications for vaccine efficacy

Current Use of Adenovirus Vectors and Their Production Methods.