The Failures of an Ideal COVID-19 Vaccine: A Simulation Study

This paper simulates an ideal COVID-19 vaccine that confers immediate sterilizing immunity against all SARS-CoV-2 variants. The purpose was to explore how well this ideal vaccine could protect a population against common conditions (such as vaccine hesitancy) that might impair vaccine effectiveness. Simulations were done with an SEIRS spreadsheet model that ran two parallel subpopulations: one that accepted vaccination, and another that refused it. The two subpopulations could transmit infections to one another. Success was judged by the rate of new cases in the period from 1-5 years after the introduction of the vaccine. Under good conditions, including a small subpopulation that refused vaccination, rapid distribution of the vaccine, duration of vaccinal immunity longer than 12 months, good retention of interest in getting vaccinated after the first year, strict maintenance of nonpharmaceutical interventions (NPIs) such as masking, and new variants with R0s less than 4.0, the vaccine was able to end the epidemic. With violation of these conditions, the post-vaccine era futures ranged from endemic COVID at a low or medium level to rates of COVID cases worse than anything seen in the US up to late 2021. The most important conditions for keeping case rates low were a fast speed of vaccine distribution, a low percentage of the population that refuses vaccination, a long duration of vaccinal immunity, and continuing maintenance of NPIs after vaccination began. On the other hand, a short duration of vaccinal immunity, abandonment of NPIs, and new variants with a high R0 were powerful barriers to disease control. New variants with high R0s were particularly damaging, producing high case rates except when vaccination speed was unrealistically rapid. A recurring finding was that most disease afflicting the vaccinated population in these simulations originated in the unvaccinated population, and cutting off interaction with the unvaccinated population caused a sharp drop in the case rate of the vaccinated population. In conclusion, multiple common conditions can compromise the effectiveness of even an ideal vaccine.

Pentavalent Disabled Infectious Single Animal (DISA)/DIVA Vaccine Provides Protection in Sheep and Cattle against Different Serotypes of Bluetongue Virus

Bluetongue (BT) is a midge-borne OIE-notifiable disease of ruminants caused by the bluetongue virus (BTV). There are at least 29 BTV serotypes as determined by serum neutralization tests and genetic analyses of genome segment 2 encoding serotype immunodominant VP2 protein. Large parts of the world are endemic for multiple serotypes. The most effective control measure of BT is vaccination. Conventionally live-attenuated and inactivated BT vaccines are available but have their specific pros and cons and are not DIVA compatible. The prototype Disabled Infectious Single Animal (DISA)/DIVA vaccine based on knockout of NS3/NS3a protein of live-attenuated BTV, shortly named DISA8, fulfills all criteria for modern veterinary vaccines of sheep. Recently, DISA8 with an internal in-frame deletion of 72 amino acid codons in NS3/NS3a showed a similar ideal vaccine profile in cattle. Here, the DISA/DIVA vaccine platform was applied for other serotypes, and pentavalent DISA/DIVA vaccine for “European” serotypes 1, 2, 3, 4, 8 was studied in sheep and cattle. Protection was demonstrated for two serotypes, and neutralization Ab titers indicate protection against other included serotypes. The DISA/DIVA vaccine platform is flexible in use and generates monovalent and multivalent DISA vaccines to combat specific field situations with respect to Bluetongue.

Nanometric Virus-Like Particles: Key Tools for Vaccine and Adjuvant Technology

The ideal vaccine should trigger a specific response against pathogens and induce the immune system memory to be prepared for eventual following infections. Although different approaches to develop new vaccines are currently taken, several of the features of natural pathogens that allow a tailored immune reaction are difficult to mimic. The viral capsids are the physical interface between a virus and the host defense machinery which recognizes specific patterns of the viral supramolecular complexes. Therefore, empty viral particles deprived of their genomes represent optimal targets to induce immune reactions with several advantages for vaccination and adjuvant realization.

Landscapes of an ideal COVID-19 vaccine

This paper discusses the designing strategies for an ideal COVID-19 vaccine. It gives an illustrative methodology of a complete immunologic understanding of an ideal vaccine that can be used to formulate and prepare a COVID-19 vaccine antigen.

Immunization with Human Cytomegalovirus Core Fusion Machinery and Accessory Envelope Proteins Elicit Strong Synergistic Neutralizing Activities

Human cytomegalovirus (HCMV) core fusion machinery proteins gB and gH/gL, and accessory proteins UL128/UL130/UL131A, are the key envelope proteins that mediate HCMV entry into and infection of host cells. To determine whether these HCMV envelope proteins could elicit neutralizing activities synergistically, we immunized rabbits with individual or various combinations of these proteins adsorbed to aluminum hydroxide mixed with CpG-ODN. We then analyzed serum neutralizing activities with multiple HCMV laboratory strains and clinical isolates. HCMV trimeric gB and gH/gL elicited high and moderate titers of HCMV neutralizing activity, respectively. HCMV gB in combination with gH/gL elicited up to 17-fold higher HCMV neutralizing activities compared to the sum of neutralizing activity elicited by the individual proteins analyzed with both fibroblasts and epithelial cells. HCMV gB+gH/gL+UL128/UL130/UL131A in combination increased the neutralizing activity up to 32-fold compared to the sum of neutralizing activities elicited by the individual proteins analyzed with epithelial cells. Adding UL128/UL130/UL131A to gB and gH/gL combination did not increase further the HCMV neutralizing activity analyzed with fibroblasts. These data suggest that the combination of HCMV core fusion machinery envelope proteins gB+gH/gL or the combination of gB and pentameric complex could be ideal vaccine candidates that would induce optimal immune responses against HCMV infection.

Virus-Like Particle Systems for Vaccine Development Against Viruses in the Flaviviridae Family

Viruses in the Flaviviridae family are important human and animal pathogens that impose serious threats to global public health. This family of viruses includes emerging and re-emerging viruses, most of which are transmitted by infected mosquito or tick bites. Currently, there is no protective vaccine or effective antiviral treatment against the majority of these viruses, and due to their growing spread, several strategies have been employed to manufacture prophylactic vaccines against these infectious agents including virus-like particle (VLP) subunit vaccines. VLPs are genomeless viral particles that resemble authentic viruses and contain critical repetitive conformational structures on their surface that can trigger the induction of both humoral and cellular responses, making them safe and ideal vaccine candidates against these viruses. In this review, we focus on the potential of the VLP platform in the current vaccine development against the medically important viruses in the Flaviviridae family.

Norovirus Capsid Protein-Derived Nanoparticles and Polymers as Versatile Platforms for Antigen Presentation and Vaccine Development

Major viral structural proteins interact homotypically and/or heterotypically, self-assembling into polyvalent viral capsids that usually elicit strong host immune responses. By taking advantage of such intrinsic features of norovirus capsids, two subviral nanoparticles, 60-valent S60 and 24-valent P24 nanoparticles, as well as various polymers, have been generated through bioengineering norovirus capsid shell (S) and protruding (P) domains, respectively. These nanoparticles and polymers are easily produced, highly stable, and extremely immunogenic, making them ideal vaccine candidates against noroviruses. In addition, they serve as multifunctional platforms to display foreign antigens, self-assembling into chimeric nanoparticles or polymers as vaccines against different pathogens and illnesses. Several chimeric S60 and P24 nanoparticles, as well as P domain-derived polymers, carrying different foreign antigens, have been created and demonstrated to be promising vaccine candidates against corresponding pathogens in preclinical animal studies, warranting their further development into useful vaccines.

Moving from Empirical to Rational Vaccine Design in the ‘Omics’ Era

An ideal vaccine provides long lasting protection against a pathogen by eliciting a well-rounded immune response which engages both innate and adaptive immunity. However, we have a limited understanding of how components of innate immunity, antibody and cell-mediated adaptive immunity interact and function together at a systems level. With advances in high-throughput ‘Omics’ methodologies it has become possible to capture global changes in the host, at a cellular and molecular level, that are induced by vaccination and infection. Analysis of these datasets has shown the promise of discovering mechanisms behind vaccine mediated protection, immunological memory, adverse effects as well as development of more efficient antigens and adjuvants. In this review, we will discuss how systems vaccinology takes advantage of new technology platforms and big data analysis, to enable the rational development of better vaccines.

Phase-variable bacterial loci: how bacteria gamble to maximise fitness in changing environments

Phase-variation of genes is defined as the rapid and reversible switching of expression — either ON-OFF switching or the expression of multiple allelic variants. Switching of expression can be achieved by a number of different mechanisms. Phase-variable genes typically encode bacterial surface structures, such as adhesins, pili, and lipooligosaccharide, and provide an extra contingency strategy in small-genome pathogens that may lack the plethora of ‘sense-and-respond’ gene regulation systems found in other organisms. Many bacterial pathogens also encode phase-variable DNA methyltransferases that control the expression of multiple genes in systems called phasevarions (phase-variable regulons). The presence of phase-variable genes allows a population of bacteria to generate a number of phenotypic variants, some of which may be better suited to either colonising certain host niches, surviving a particular environmental condition and/or evading an immune response. The presence of phase-variable genes complicates the determination of an organism's stably expressed antigenic repertoire; many phase-variable genes are highly immunogenic, and so would be ideal vaccine candidates, but unstable expression due to phase-variation may allow vaccine escape. This review will summarise our current understanding of phase-variable genes that switch expression by a variety of mechanisms, and describe their role in disease and pathobiology.