Second-generation Vaccines Research Articles

Comparative analysis of asymptomatic infection prevalence in Beta, Delta, and Omicron surges of COVID-19

BackgroundThe COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had a devastating impact on the global population, with an estimated 650 million people infected and more than 6.6 million lives lost. Asymptomatic individuals have been shown to play a significant role in the transmission of the virus. Therefore, this study aims to investigate and compare the prevalence of asymptomatic individuals across three waves associated with the Beta, Delta, and Omicron variants of the virus. MethodsThis retrospective study was conducted between December 2020 and March 2022. The study population consisted of passengers on international flights who were referred to the Gerash Clinical and Molecular Diagnosis Laboratory. Real-time PCR was employed for the diagnosis of SARS-CoV-2. ResultsOut of a total of 8592 foreign travelers referred to our laboratory, 139 (1.16 %) tested positive for SARS-CoV-2 infection and were asymptomatic. During the Beta surge, 35 (1.49 %) out of 2335 passengers tested positive for SARS-CoV-2. In the Delta surge, 31 (0.6 %) out of 5127 passengers tested positive. However, during the Omicron surge, a significantly higher number of passengers, specifically 73 (6.46 %) out of 1130, had a positive result for the SARS-CoV-2 test. ConclusionConsidering the significant role of asymptomatic transmission in the spread of COVID-19, it is imperative to reconsider health policies when dealing with future surges of the Omicron subvariants. Additionally, we strongly recommend that the World Health Organization prioritize the development and distribution of second-generation vaccines that target not only disease but also infection prevention.

Vaccines for Orthopoxviruses: A Review

Human and animal infections with Orthopoxvirus have become more prevalent in recent years. Although smallpox has been eradicated, vaccinations continue to play a role in controlling the spread of Orthopoxvirus diseases. First generation vaccines were successfully commercialized, and they were widely used previously. Besides, several second-generation vaccines that emphasize sterile cell culture techniques for vaccine production have been developed. Some of the third-generation vaccines also successfully trigger immune responses in the host, and they are being researched as safer substitutes for smallpox vaccines. Extensive work is still being done on the creation of fourth-generation smallpox vaccines, which include the creation of DNA subunit vaccines. Clinical studies must be conducted to evaluate the efficacies of these vaccines. Vaccine was effective in preventing smallpox infection. To achieve the Sustainable Development Goals of the United Nations, a new paradigm for vaccination research and product development must be established.

A Single-Dose Intranasal Combination Panebolavirus Vaccine.

Ebolaviruses Ebola (EBOV), Sudan (SUDV), and Bundibugyo (BDBV) cause severe human disease, which may be accompanied by hemorrhagic syndrome, with high case fatality rates. Monovalent vaccines do not offer cross-protection against these viruses whose endemic areas overlap. Therefore, development of a panebolavirus vaccine is a priority. As a vaccine vector, human parainfluenza virus type 3 (HPIV3) has the advantages of needle-free administration and induction of both systemic and local mucosal antibody responses in the respiratory tract. To minimize the antivector immunity, genes encoding the HPIV3 envelope proteins F and HN were removed from the vaccine constructs, resulting in expression of only the ebolavirus envelope protein-glycoprotein. These second-generation vaccine constructs were used to develop a combination vaccine against EBOV, SUDV, and BDBV. A single intranasal vaccination of guinea pigs or ferrets with the trivalent combination vaccine elicited humoral responses to each of the targeted ebolaviruses, including binding and neutralizing antibodies, as well as Fc-mediated effector functions. This vaccine protected animals from death and disease caused by lethal challenges with EBOV, SUDV, or BDBV. The combination vaccine elicited protection that was comparable to that induced by the monovalent vaccines, thus demonstrating the value of this combination trivalent vaccine.

Preclinical evaluation of PHH-1V vaccine candidate against SARS-CoV-2 in non-human primates

SARS-CoV-2 emerged in December 2019 and quickly spread worldwide, continuously striking with an unpredictable evolution. Despite the success in vaccine production and mass vaccination programs, the situation is not still completely controlled, and therefore accessible second-generation vaccines are required to mitigate the pandemic. We previously developed an adjuvanted vaccine candidate coded PHH-1V, based on a heterodimer fusion protein comprising the RBD domain of two SARS-CoV-2 variants. Here, we report data on the efficacy, safety, and immunogenicity of PHH-1V in cynomolgus macaques. PHH-1V prime-boost vaccination induces high levels of RBD-specific IgG binding and neutralizing antibodies against several SARS-CoV-2 variants, as well as a balanced Th1/Th2 cellular immune response. Remarkably, PHH-1V vaccination prevents SARS-CoV-2 replication in the lower respiratory tract and significantly reduces viral load in the upper respiratory tract after an experimental infection. These results highlight the potential use of the PHH-1V vaccine in humans, currently undergoing Phase III clinical trials.

The Global Monkeypox (Mpox) Outbreak: A Comprehensive Review.

Monkeypox (Mpox) is a contagious illness that is caused by the monkeypox virus, which is part of the same family of viruses as variola, vaccinia, and cowpox. It was first detected in the Democratic Republic of the Congo in 1970 and has since caused sporadic cases and outbreaks in a few countries in West and Central Africa. In July 2022, the World Health Organization (WHO) declared a public-health emergency of international concern due to the unprecedented global spread of the disease. Despite breakthroughs in medical treatments, vaccines, and diagnostics, diseases like monkeypox still cause death and suffering around the world and have a heavy economic impact. The 85,189 reported cases of Mpox as of 29 January 2023 have raised alarm bells. Vaccines for the vaccinia virus can protect against monkeypox, but these immunizations were stopped after smallpox was eradicated. There are, however, treatments available once the illness has taken hold. During the 2022 outbreak, most cases occurred among men who had sex with men, and there was a range of 7-10 days between exposure and the onset of symptoms. Three vaccines are currently used against the Monkeypox virus. Two of these vaccines were initially developed for smallpox, and the third is specifically designed for biological-terrorism protection. The first vaccine is an attenuated, nonreplicating smallpox vaccine that can also be used for immunocompromised individuals, marketed under different names in different regions. The second vaccine, ACAM2000, is a recombinant second-generation vaccine initially developed for smallpox. It is recommended for use in preventing monkeypox infection but is not recommended for individuals with certain health conditions or during pregnancy. The third vaccine, LC16m8, is a licensed attenuated smallpox vaccine designed to lack the B5R envelope-protein gene to reduce neurotoxicity. It generates neutralizing antibodies to multiple poxviruses and broad T-cell responses. The immune response takes 14 days after the second dose of the first two vaccines and 4 weeks after the ACAM2000 dose for maximal immunity development. The efficacy of these vaccines in the current outbreak of monkeypox is uncertain. Adverse events have been reported, and a next generation of safer and specific vaccines is needed. Although some experts claim that developing vaccines with a large spectrum of specificity can be advantageous, epitope-focused immunogens are often more effective in enhancing neutralization.

Glycosylated nanoparticle-based PfCSP vaccine confers long-lasting antibody responses and sterile protection in mouse malaria model

The development of an effective and durable vaccine remains a central goal in the fight against malaria. Circumsporozoite protein (CSP) is the major surface protein of sporozoites and the target of the only licensed Plasmodium falciparum (Pf) malaria vaccine, RTS,S/AS01. However, vaccine efficacy is low and short-lived, highlighting the need for a second-generation vaccine with superior efficacy and durability. Here, we report a Helicobacter pylori apoferritin-based nanoparticle immunogen that elicits strong B cell responses against PfCSP epitopes that are targeted by the most potent human monoclonal antibodies. Glycan engineering of the scaffold and fusion of an exogenous T cell epitope enhanced the anti-PfCSP B cell response eliciting strong, long-lived and protective humoral immunity in mice. Our study highlights the power of rational vaccine design to generate a highly efficacious second-generation anti-infective malaria vaccine candidate and provides the basis for its further development.

Mucosal immunization with Ad5-based vaccines protects Syrian hamsters from challenge with omicron and delta variants of SARS-CoV-2.

SARS-CoV-2 variant clades continue to circumvent antibody responses elicited by vaccination or infection. Current parenteral vaccination strategies reduce illness and hospitalization, yet do not significantly protect against infection by the more recent variants. It is thought that mucosal vaccination strategies may better protect against infection by inducing immunity at the sites of infection, blocking viral transmission more effectively, and significantly inhibiting the evolution of new variants of concern (VOCs). In this study, we evaluated the immunogenicity and efficacy of a mucosally-delivered, non-replicating, adenovirus type 5-vectored vaccine that expresses the spike (S) gene of Wuhan (rAd5-S-Wuhan), delta (rAd5-S-delta), or omicron (rAd5-S-omicron) SARS-CoV-2 VOCs. Hamsters were immunized with these vaccines intranasally prior to challenge with omicron or delta variants. Additionally, one group was vaccinated by oral gavage with rAd5-S-Wuhan prior to challenge with the delta variant. Both intranasal and oral administration of rAd5-S-Wuhan generated cross-reactive serum IgG and mucosal IgA to all variant spike and RBD proteins tested. rAd5-S-omicron and rAd5-S-delta additionally elicited cross-reactive antibodies, though rAd5-S-omicron had significantly lower binding antibody levels except against its matched antigens. Two weeks after the final vaccination, hamsters were challenged with a SARS-CoV-2 variant; omicron or delta. Whether matched to the challenge or with rAd5-S-Wuhan, all vaccines protected hamsters from weight loss and lung pathology caused by challenge and significantly reduced viral shedding compared to placebo. Vaccination with rAd5-S-Wuhan provided significant protection, although there was an improved reduction in shedding and disease pathology in groups protected by the matched VOC vaccines. Nevertheless, Wuhan-based vaccination elicited the most cross-reactive antibody responses generally. Overall, heterologous vaccination via mucosal routes may be advantageous for second-generation vaccines.

Safety and immunogenicity of the group B streptococcus vaccine AlpN in a placebo-controlled double-blind phase 1 trial

Group B streptococcus (GBS) is a leading cause of life-threatening neonatal infections and subsets of adverse pregnancy outcomes. Essentially all GBS strains possess one allele of the alpha-like protein (Alp) family. A maternal GBS vaccine, consisting of the fused N-terminal domains of the Alps αC and Rib (GBS-NN), was recently demonstrated to be safe and immunogenic in healthy adult women. To enhance antibody responses to all clinically relevant Alps, a second-generation vaccine has been developed (AlpN), also containing the N-terminal domain of Alp1 and the one shared by Alp2 and Alp3. In this study, the safety and immunogenicity of AlpN is assessed in a randomized, double-blind, placebo-controlled, and parallel-group phase I study, involving 60 healthy non-pregnant women. AlpN is well tolerated and elicits similarly robust and persistent antibody responses against all four Alp-N-terminal domains, resulting in enhanced opsonophagocytic killing of all Alp serotypes covered by the vaccine.

An RNA-Based Vaccine Platform for Use against Mycobacterium tuberculosis.

Mycobacterium tuberculosis (M.tb), a bacterial pathogen that causes tuberculosis disease (TB), exerts an extensive burden on global health. The complex nature of M.tb, coupled with different TB disease stages, has made identifying immune correlates of protection challenging and subsequently slowing vaccine candidate progress. In this work, we leveraged two delivery platforms as prophylactic vaccines to assess immunity and subsequent efficacy against low-dose and ultra-low-dose aerosol challenges with M.tb H37Rv in C57BL/6 mice. Our second-generation TB vaccine candidate ID91 was produced as a fusion protein formulated with a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant in a stable emulsion) or as a novel replicating-RNA (repRNA) formulated in a nanostructured lipid carrier. Protein subunit- and RNA-based vaccines preferentially elicit cellular immune responses to different ID91 epitopes. In a single prophylactic immunization screen, both platforms reduced pulmonary bacterial burden compared to the controls. Excitingly, in prime-boost strategies, the groups that received heterologous RNA-prime, protein-boost or combination immunizations demonstrated the greatest reduction in bacterial burden and a unique humoral and cellular immune response profile. These data are the first to report that repRNA platforms are a viable system for TB vaccines and should be pursued with high-priority M.tb antigens containing CD4+ and CD8+ T-cell epitopes.

Impact of antigenic evolution and original antigenic sin on SARS-CoV-2 immunity.

Infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and vaccinations targeting the spike protein (S) offer protective immunity against coronavirus disease 2019 (COVID-19). This immunity may further be shaped by cross-reactivity with common cold coronaviruses. Mutations arising in S that are associated with altered intrinsic virus properties and immune escape result in the continued circulation of SARS-CoV-2 variants. Potentially, vaccine updates will be required to protect against future variants of concern, as for influenza. To offer potent protection against future variants, these second-generation vaccines may need to redirect immunity to epitopes associated with immune escape and not merely boost immunity toward conserved domains in preimmune individuals. For influenza, efficacy of repeated vaccination is hampered by original antigenic sin, an attribute of immune memory that leads to greater induction of antibodies specific to the first-encountered variant of an immunogen compared with subsequent variants. In this Review, recent findings on original antigenic sin are discussed in the context of SARS-CoV-2 evolution. Unanswered questions and future directions are highlighted, with an emphasis on the impact on disease outcome and vaccine design.

Vaccination Approach Toward Monkeypox: An Urgent Call

Vaccination Approach Toward Monkeypox: An Urgent Call

Mpox: What Practicing Gastroenterologists Need to Know

Mpox: What Practicing Gastroenterologists Need to Know

Plants That Can be Used as Plant-Based Edible Vaccines; Current Situation and Recent Developments

Among the purposes of genetic engineering technology applications in plants, improving product quality, increasing resistance to harmful organisms and improving agronomic properties, the most important one is the production of drugs, hormones and vaccines for humans and animals (for example, the use of potatoes in cholera vaccines). Today, the use of plants as bioreactors to obtain recombinant proteins from plants has been further developed and accelerated thanks to the developments in plant genetics, molecular biology and biotechnology. Appearing as a concept about a decade ago, plant bioreactors are genetically modified plants whose genomes have been manipulated to incorporate and express gene sequences of a number of useful proteins from different biological sources. Plant-derived bioreactor systems offer significant advantages over techniques used for other biological-based protein production. Easy and inexpensive production from plant tissues, providing appropriate post-translational modifications for the production of recombinant viral and bacterial antigens, and showing similar biological activity to recombinant vaccines obtained in microorganisms are important reasons that encourage the use of plant tissues in vaccine production. Edible vaccines, which create an immune response in the body against a foreign pathogen that causes disease, have a working mechanism that serves as both a nutritive and a vaccine that we consume in our daily lives. In the development of edible vaccines, the gene responsible for the production of the part of the foreign pathogen that causes the disease, that is, the antigen, which provides the immune response in the body, is transferred to the plants. With this technique, antigen production is carried out in plants. For example, thanks to today's advancing technology, enough hepatitis B antigens to vaccinate all of the world's approximately 133 million live births each year can be grown on a field of approximately two hundred hectares. In addition to these, edible vaccine technology also makes edible vaccines an interesting concept as secondgeneration vaccines, as they allow several antigens to approach M (microcoat) cells at the same time, by offering multicomponent vaccine proteins that are possible by crossing two plant lines.

Immunologische aspecten van Covid-19-ziekte en van vaccinatie tegen SARS-CoV-2 Deel 2: Variaties van het immuunantwoord individueel en in de tijd bij een infectie met SARS-CoV-2 en bij vaccinatie

Individual variations in the immune response in Covid-19 infection or after vaccination and quantitative changes with time Pronounced individual differences in immune responses following a SARS-CoV-2 infection or COVID-19 vaccination have been noticed. Importantly, an early and profound T cell response to the virus with the production of high amounts of interferon-gamma (IFN-γ) and interleukin-2 (IL-2) and low amounts of tumor necrosis factor-alpha (TNF-α) results in asymptomatic or mild disease, in contrast to what happens in patients getting seriously ill. In order to develop efficient vaccines and targeted immunization schedules, it is important to measure T cell responses and the antibody production induced by the various vaccines, since the immune response depends on not yet fully defined genetic properties, age, comorbidities, used medication, etc. The strongest recall is seen in convalescent persons after vaccination (‘hybrid immunity’). Because of waning of the immunity and the continuous emergence of virus variants, regular repeat vaccinations and the development of stronger second-generation vaccines, maybe with the recognition of a more extended antigen spectrum, appear necessary. Special attention should be given to high-risk patients.

Artificial Cell Membrane Polymersome-Based Intranasal Beta Spike Formulation as a Second Generation Covid-19 Vaccine.

Current parenteral coronavirus disease 2019 (Covid-19) vaccines inadequately protect against infection of the upper respiratory tract. Additionally, antibodies generated by wild type (WT) spike-based vaccines poorly neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. To address the need for a second-generation vaccine, we have initiated a preclinical program to produce and evaluate a potential candidate. Our vaccine consists of recombinant Beta spike protein coadministered with synthetic CpG adjuvant. Both components are encapsulated within artificial cell membrane (ACM) polymersomes, synthetic nanovesicles efficiently internalized by antigen presenting cells, including dendritic cells, enabling targeted delivery of cargo for enhanced immune responses. ACM vaccine is immunogenic in C57BL/6 mice and Golden Syrian hamsters, evoking high serum IgG and neutralizing responses. Compared to an ACM-WT spike vaccine that generates predominantly WT-neutralizing antibodies, the ACM-Beta spike vaccine induces antibodies that neutralize WT and Beta viruses equally. Intramuscular (IM)-immunized hamsters are strongly protected from weight loss and other clinical symptoms after the Beta challenge but show delayed viral clearance in the upper airway. With intranasal (IN) immunization, however, neutralizing antibodies are generated in the upper airway concomitant with rapid and potent reduction of viral load. Moreover, antibodies are cross-neutralizing and show good activity against Omicron. Safety is evaluated in New Zealand white rabbits in a repeated dose toxicological study under Good Laboratory Practice (GLP) conditions. Three doses, IM or IN, at two-week intervals do not induce an adverse effect or systemic toxicity. Cumulatively, these results support the application for a Phase 1 clinical trial of ACM-polymersome-based Covid-19 vaccine (ClinicalTrials.gov identifier: NCT05385991).

Dengue vaccine development: challenges and prospects.

Dengue vaccine development is a high public health priority. To date, no dengue vaccine is in widespread use. Here we review the challenges in dengue development and the latest results for the second-generation dengue vaccines. The biggest hurdle is the immunological interaction between the four antigenically distinct dengue serotypes. The advantages of second-generation dengue vaccines are the inclusion of nonstructural proteins of the dengue backbone and a more convenient dosing with reduced numbers of doses needed. Although dengue-primed individuals can already benefit from vaccination with the first licensed dengue vaccine CYD-TDV, the public health need for the dengue-naive population has not yet been met. The urgent need remains to identify correlates of both protection and enhancement; until such correlates have been identified, all second-generation dengue vaccines still need to go through full phase 3 trials. The 5-year efficacy and safety data for both second-generation dengue vaccines are imminent.

Nucleic Acid Vaccines

DNA vaccines, a type of nucleic acid vaccine, have emerged as one of the recent developments in immunology and recombinant DNA technology, offering great potential in terms of ease of manufacture, maintenance, and safety compared to conventional vaccines. Since their discovery, DNA vaccines have evolved immensely, resulting in the employment of new techniques such as gene guns, in vivo electroporation, and nanoparticle-based carriers to enhance the delivery of vaccines into the cells. Starting from the failures of the first-generation DNA vaccines to the near-success second-generation vaccines, several strategies including codon optimization, antigen design, and heterologous prime-boost have greatly helped in strengthening the vaccine's immunogenicity. The purpose of developing these third-generation vaccines is primarily to solve existing medical complications like cancer, along with therapeutic uses, to address health problems, and to aid the rapid eradication of sudden global outbreaks of infectious diseases including Ebola and COVID-19. In this review, we focus on the recent developments and strategies employed to improve the efficacy of DNA vaccines and discuss their mechanism of action, potential concerns, progress achieved, and a brief update on its clinical applications.

Repositioning potentials of smallpox vaccines and antiviral agents in monkeypox outbreak: A rapid review on comparative benefits and risks.

Background and aimsThere is a sought for vaccines and antiviral agents as countermeasures for the recent monkeypox outbreak. Here, we aimed to review and discuss the repurposing potentials of smallpox vaccines and drugs in monkeypox outbreaks based on their comparative benefits and risks. Therefore, we conducted this rapid review and discussed the repurposing potentials of smallpox vaccines and drugs in monkeypox infection.MethodsHere, we searched Google Scholar and PubMed for relevant information and data. We found many articles that have suggested the use of smallpox vaccines and antiviral drugs in monkeypox outbreaks according to the study findings. We read the relevant articles to extract information.ResultsAccording to the available documents, we found two replication‐competent and one replication‐deficient vaccinia vaccines were effective against Orthopoxvirus. However, the healthcare authorities have authorized second‐generation live vaccina virus vaccines against Orthopoxvirus in many countries. Smallpox vaccine is almost 85% effective in preventing monkeypox infection as monkeypox virus, variola virus, and vaccinia virus are similar. The United States and Canada have approved a replication‐deficient third‐generation smallpox vaccine for the prevention of monkeypox infection. However, the widely used second‐generation smallpox vaccines contain a live virus and replicate it into the human cell. Therefore, there is a chance to cause virus‐induced complications among the vaccinated subjects. In those circumstances, the available Orthopoxvirus inhibitors might be a good choice for treating monkeypox infections as they showed similar efficacy in monkeypox infection in different animal model clinical trials. Also, the combined use of antiviral drugs and vaccinia immune globulin can enhance significant effectiveness in immunocompromised subjects.ConclusionRepurposing of these smallpox vaccines and antiviral agents might be weapons to fight monkeypox infection. Also, we recommend further investigations of smallpox vaccines and Orthopoxvirus inhibitors in a human model study to explore their exact role in human monkeypox infections.

Insights into induction of the immune response by the hepatitis B vaccine.

After more than four decades of hepatitis B virus (HBV) vaccine implementation, its safety and efficacy in preventing HBV infection have been proven and several milestones have been achieved. Most countries have included HBV immunization schedules in their health policies and progress has been made regarding universalization of the first HBV vaccine dose at birth. All of these actions have significantly contributed to reducing both the incidence of HBV infection and its related complications. However, there are still many drawbacks to overcome. The main concerns are the deficient coverage rate of the dose at birth and the large adult population that has not been reached timely by universal immunization. Additionally, the current most widely used second-generation vaccines do not induce protective immunity in 5% to 10% of the population, particularly in people over 40-years-old, obese (body mass index > 25 kg/m2), heavy smokers, and patients undergoing dialysis or infection with human immunodeficiency virus. Recently developed and approved novel vaccine formulations using more potent adjuvants or multiple antigens have shown better performance, particularly in difficult settings. These advances re-launch the expectations of achieving the World Health Organization’s objective of completing hepatitis control by 2030.

Modelling the impact of Omicron and emerging variants on SARS-CoV-2 transmission and public health burden

BackgroundSARS-CoV-2 variants of concern, such as Omicron (B.1.1.529), continue to emerge. Assessing the impact of their potential viral properties on the probability of future transmission dominance and public health burden is fundamental in guiding ongoing COVID-19 control strategies.MethodsWith an individual-based transmission model, OpenCOVID, we simulated three viral properties; infectivity, severity, and immune-evading ability, all relative to the Delta variant, to identify thresholds for Omicron’s or any emerging VOC’s potential future dominance, impact on public health, and risk to health systems. We further identify for which combinations of viral properties current interventions would be sufficient to control transmission.ResultsWe show that, with first-generation SARS-CoV-2 vaccines and limited physical distancing in place, a VOC’s potential future dominance is primarily driven by its infectivity, which does not always lead to an increased public health burden. However, we also show that highly immune-evading variants that become dominant, even in the case of reduced variant severity, would likely require alternative measures to avoid strain on health systems, such as strengthened physical distancing measures, novel treatments, and second-generation vaccines. Expanded vaccination, that includes a booster dose for adults and child vaccination strategies, is projected to have the biggest public health benefit for a highly infective, highly severe VOC with low immune-evading capacity.ConclusionsThese findings provide quantitative guidance to decision-makers at a critical time while Omicron’s properties are being assessed and preparedness for emerging VOCs is eminent. We emphasise the importance of both genomic and population epidemiological surveillance.