Can immunological principles and cross-disciplinary science illuminate the path to vaccines for HIV and other global health challenges?

Vaccines are one of the most impactful and cost-effective public health measures of the twentieth century. However, there remain great unmet needs to develop vaccines for globally burdensome infectious diseases and to allow more timely responses to emerging infectious disease threats. Recent advances in the understanding of immunological principles operative not just in model systems but in humans in concert with the development and application of powerful new tools for profiling human immune responses, in our understanding of pathogen variation and evolution, and in the elucidation of the structural aspects of antibody–pathogen interactions, have illuminated pathways by which these unmet needs might be addressed. Using these advances as foundation, we herein present a conceptual framework by which the discovery, development and iterative improvement of effective vaccines for HIV, malaria and other globally important infectious diseases might be accelerated.     

Group B Streptococcus: global incidence and vaccine development

An ongoing public health challenge is to develop vaccines that are effective against infectious diseases that have global relevance. Vaccines against serotypes of group B Streptococcus (GBS) that are prevalent in the United States and Europe are not optimally efficacious against serotypes common to other parts of the world. New technologies and innovative approaches are being used to identify GBS antigens that overcome serotype-specificity and that could form the basis of a globally effective vaccine against this opportunistic pathogen. This Review highlights efforts towards this goal and describes a template that can be followed to develop vaccines against other bacterial pathogens.     

Global sharing of COVID-19 vaccines: A duty of justice,not charity

Global scarcity of COVID-19 vaccines raises ethical questions about their fair allocation between nations. Section I introduces the question and proposes that wealthy nations have a duty of justice to share globally scarce COVID-19 vaccines. Section II distinguishes justice from charity and argues that beneficiaries of unjust structures incur duties of justice when they are systematically advantaged at others expense. Section III gives a case-based argument describing three upstream structural injustices that systematically advantaged wealthy countries and disadvantaged poorer countries, contributing to global disparities of COVID-19 vaccines. Section IV examines more closely the duties of justice owed, including a duty to relinquish holdings, restitute victims, and restore relationships. Section V concludes that wealthy nations have a duty of justice to share COVID-19 vaccines with poor nations and to restore relationships damaged by injustice. All nations should take steps to transform unjust structures.     

Latent Mycobacterium tuberculosis-persistence, patience, and winning by waiting

Mycobacterium tuberculosis is a globally successful pathogen due to its ability to persist for long periods of time unrecognized by the human immune system. The panoply of genes that allows the organism to enter latency and then re-emerge later during endogenous reinfection are now being elucidated. Novel antimicrobials and vaccines will need to target these mycobacterial pathogenic mechanisms to suceed against tuberculosis.     

How poliomyelitis is to be eradicated completely

In 1988 the World Health Assembly resolved to eradicate poliomyelitis globally by the year 2000. The work continues. The problem arose how to quit the system of mass immunization with oral poliovirus vaccine (OPV) without trouble and to achieve the disappearance of polioviruses worldwide. After the cessation of the OPV use a certain number of vaccine viruses may remain that will circulate among the ever growing number of nonimmune population. Live enterovirus vaccines prepared from nonpathogenic serotypes of ECHO virus are proposed for application to stop the circulation of vaccine poliovirus. These vaccines will make it possible to eliminate the remaining vaccine viruses from circulation and to complete the process of worldwide poliomyelitis eradication.     

An epidemiological model for direct and indirect transmission of typhoid fever

The modified SIS epidemiological model considers the usual direct transmission (short cycle) and indirect transmission (long cycle) of typhoid fever. Thresholds are determined, and the equilibrium points are shown to be globally stable. Local stability of the equilibrium points is shown in the corresponding model with vaccines. After estimating parameters using current statistical data for typhoid fever in Chile, computer simulations are used to obtain the numerical behavior of this disease and to estimate the effect of several control policies.     

Boosting Global Yellow Fever Vaccine Supply for Epidemic Preparedness: 3 Actions for China and the USA

<正>Yellow fever(YF) is an acute disease caused by a flavivirus that infects the liver. It can cause jaundice, bleeding, kidney damage, and death. No antiviral therapy exists.A vaccine does exist, however, and fortunately confers lifelong immunity after a single dose(Monath et al. 2016;WHO 2017 a, b).YF is transmitted by mosquitoes in two main cycles. In     

Advances in the development of Salmonella-based vaccine strategies for protection against Salmonellosis in humans

Salmonella spp. are important human pathogens globally causing millions of cases of typhoid fever and non-typhoidal salmonellosis annually. There are only a few vaccines licensed for use in humans which all target Salmonella enterica serovar Typhi. Vaccine development is hampered by antigenic diversity between the thousands of serovars capable of causing infection in humans. However, a number of attenuated candidate vaccine strains are currently being developed. As facultative intracellular pathogens with multiple systems for transporting effector proteins to host cells, attenuated Salmonella strains can also serve as ideal tools for the delivery of foreign antigens to create multivalent live carrier vaccines for simultaneous immunization against several unrelated pathogens. Further, the ease with which Salmonella can be genetically modified and the extensive knowledge of the virulence mechanisms of this pathogen means that this bacterium has often served as a model organism to test new approaches. In this review we focus on (1) recent advances in live attenuated Salmonella vaccine development, (2) improvements in expression of foreign antigens in carrier vaccines and (3) adaptation of attenuated strains as sources of purified antigens and vesicles that can be used for subunit and conjugate vaccines or together with attenuated vaccine strains in heterologous prime-boosting immunization strategies. These advances have led to the development of new vaccines against Salmonella which have or will soon be tested in clinical trials.     

Contribution of the GAVI Alliance to improving health and reducing poverty

The Global Alliance for Vaccines and Immunization (GAVI), now 10 years old, was established as a successful and innovative public-private partnership to deal with a fundamental inequity. The poorest children in the poorest parts of the world were being denied access to life-saving vaccines simply on the basis of cost. GAVI has been successful in mobilizing significant funding from donors and through innovative financing instruments, immunizing large numbers of children. GAVI has been less successful, at least in the time frames first envisaged, at quickly reducing the prices of new and under-used vaccines to levels affordable by the poorest countries. Vaccines remain some of the most cost effective of public health interventions. As GAVI seeks to introduce a new set of vaccines to tackle major killers such as pneumonia and diarrhoea, and emerging threats such as cervical cancer, it needs to raise significant additional funds. There is no single solution. Multiple and new instruments will be required to raise finance both globally and at the country level, and also to incentivize industry and others to provide vaccines at affordable prices to the poorest countries.     

Immune response against Mycobacterium tuberculosis: implications for vaccine development

Tuberculosis remains a major health problem globally. Although this threat would best be controlled by a combination of chemotherapy and vaccination, satisfactory vaccines are not available yet. Rational design of a novel vaccine generation against tuberculosis has become possible on the basis of recent achievements in molecular genetics of the pathogen and immunology of the host. Currently, two different strategies are pursued. First, the subunit vaccine approach attempting to induce efficacious immunity by unique antigens in defined adjuvants. Second, the whole bacterial vaccine approach relying on multiple antigens and built-in adjuvanticity. Time will tell which type of vaccine is best suited for eradication of tuberculosis.     

A mouse-based assay for the pre-clinical neurovirulence assessment of vaccinia virus-based smallpox vaccines

Post-vaccinal encephalitis, although relatively uncommon, is a known adverse event associated with many live, attenuated smallpox vaccines. Although smallpox vaccination ceased globally in 1980, vaccine manufacture has resumed in response to concerns over the possible use of smallpox virus as an agent of bioterrorism. To better support the production of safer smallpox vaccines, we previously reported the development of a mouse model in which a relatively attenuated vaccine strain (Dryvax^®) could be discerned from a more virulent laboratory strain (WR). Here we have further tested the performance of this assay by evaluating the neurovirulence of several vaccinia virus-based smallpox vaccines spanning a known range in neurovirulence for humans. Our data indicate that testing of 10–100 pfu of virus in mice following intracranial inoculation reliably assesses the virus's neurovirulence potential for humans.     

The evolutionary consequences of alternative types of imperfect vaccines

The emergence and spread of mutant pathogens that evade the effects of prophylactic interventions, including vaccines, threatens our ability to control infectious diseases globally. Imperfect vaccines (e.g. those used against influenza), while not providing life-long immunity, confer protection by reducing a range of pathogen life-history characteristics; conversely, mutant pathogens can gain an advantage by restoring the same range of traits in vaccinated hosts. Using an SEIR model motivated by equine influenza, we investigate the evolutionary consequences of alternative types of imperfect vaccination, by comparing the spread rate of three types of mutant pathogens, in response to three types of vaccines. All mutant types spread faster in response to a transmission-blocking vaccine, relative to vaccines that reduce the proportion of exposed vaccinated individuals becoming infectious, and to vaccines that reduce the length of the infectious period; this difference increases with increasing vaccine efficacy. We interpret our results using the first published Price equation formulation for an SEIR model, and find that our main result is explained by the effects of vaccines on the equilibrium host distribution across epidemiological classes. In particular, the proportion of vaccinated infectious individuals among all exposed and infectious hosts, which is relatively higher in the transmission-blocking vaccine scenario, is important in explaining the faster spread of mutant strains in response to that vaccine. Our work illustrates the connection between epidemiological and evolutionary dynamics, and the need to incorporate both in order to explain and interpret findings of complicated infectious disease dynamics.     

Virology of the family Togaviridae

Many pathogens important for medicine, veterinary medicine or public health belong to the genera alphavirus and rubivirus within the family Togaviridae. 29 species of alphaviruses have been reported, and most of them are arboviruses. Chikungnya virus re-emerged in Kenya in 2004 and the epidemics spread to the Indian Ocean islands and many countries in South Asia, South-East Asia and Europe. On the other hand, rubella virus, a sole member of the genus rubivirus, is the causative agent of rubella and congenital rubella syndrome (CRS). Because human is only a natural host of the virus and effective live attenuated vaccines are available, immunization activities are strengthened globally to eliminate rubella and CRS, together with measles.     

Current advances in the development of SARS-CoV-2 vaccines

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now a global pandemic that has wreaked havoc globally, which has put a heavy toll on public health, lives, and the world economy. Vaccination is considered as one of the greatest successes in medical history. Based on prior experience with the development of SARS-CoV vaccines, all COVID-19 vaccines must be subjected to the tests for protective effects and harmful risks derived from antibody-dependent enhancement that may contribute to augmented infectivity and/or eosinophilic infiltration. The SARS-CoV-2 vaccine is now being developed urgently in several different ways. China is regarded as one of the world''s leading countries in SARS-CoV-2 vaccine development, up to date the last inactivated vaccine international clinical (Phase III) trial was launched in the United Arab Emirates by Sinopharm China National Biotec Group (CNBG). In this review, we outline the current status of vaccine development against clinically relevant SARS-CoV-2 strains, anticipating that such attempts would help create efficacious and sage SARS-CoV-2 vaccines.     

Complete genome sequence of ikoma lyssavirus

Lyssaviruses (family Rhabdoviridae) constitute one of the most important groups of viral zoonoses globally. All lyssaviruses cause the disease rabies, an acute progressive encephalitis for which, once symptoms occur, there is no effective cure. Currently available vaccines are highly protective against the predominantly circulating lyssavirus species. Using next-generation sequencing technologies, we have obtained the whole-genome sequence for a novel lyssavirus, Ikoma lyssavirus (IKOV), isolated from an African civet in Tanzania displaying clinical signs of rabies. Genetically, this virus is the most divergent within the genus Lyssavirus. Characterization of the genome will help to improve our understanding of lyssavirus diversity and enable investigation into vaccine-induced immunity and protection.     

Cattle tick vaccines: Many candidate antigens,but will a commercially viable product emerge?

The cattle tick, Rhipicephalus microplus, is arguably the world's most economically important external parasite of cattle. Sustainable cattle tick control strategies are required to maximise the productivity of cattle in both large production operations and small family farms. Commercially available synthetic acaricides are commonly used in control and eradication programs, but indiscriminate practices in their application have resulted in the rapid evolution of resistance among populations in tropical and subtropical regions where the invasive R. microplus thrives. The need for novel technologies that could be used alone or in combination with commercially available synthetic acaricides is driving a resurgence of cattle tick vaccine discovery research efforts by various groups globally. The aim is to deliver a next-generation vaccine that has an improved efficacy profile over the existing Bm86-based cattle tick vaccine product. We present a short review of these projects and offer our opinion on what constitutes a good target antigen and vaccine, and what might influence the market success of candidate vaccines. The previous experience with Bm86-based vaccines offers perspective on marketing and producer acceptance aspects that a next-generation cattle tick vaccine product must meet for successful commercialisation.     

Flavobacterium psychrophilum vaccine development: a difficult task

Bacterial cold water disease (BCWD) is a globally distributed freshwater fish disease caused by the Gram-negative bacterium Flavobacterium psychrophilum. It is a particularly devastating infection in fry salmonids and may lead to high levels of mortality. In spite of its economic impact on fish farms, neither the biology of the bacterium nor the bacterium–host interactions are well understood. This review provides a synopsis of the major problems related to critical remaining questions about research into the use of vaccines against F. psychrophilum and the development of a commercial vaccine against this disease. Studies using sera from convalescent rainbow trout have shown the antigenic properties of different proteins such as OmpH, OmpA and FspA, as well as low and high molecular mass lipopolysaccharide of F. psychrophilum, which are potential candidates for subunit vaccines. Inactivated F. psychrophilum bacterins have been successfully tested as vaccines under laboratory conditions by both immersion and intraperitoneal routes. However, the efficacy and the practical usefulness of these preparations still have to be proved. The use of attenuated and wild-type strains to immunize fish showed that these systems offer high levels of protection. Nevertheless, their application clashes with the regulations for environmental protection in many countries. In conclusion, protective vaccines against BCWD are theoretically possible, but substantial efforts still have to be made in order to permit the development of a commercial vaccine.     

Identification of antigens for the development of a subunit vaccine against Photobacterium damselae ssp. piscicida

Photobacterium damselae ssp. piscicida (Ph.d.p.), the causative agent of photobacteriosis, is among the most important pathogens affecting finfish aquaculture globally. With the emergence of recombinant technology, subunit vaccines have been actively pursued, but mostly for viral diseases. Bacterial subunit vaccines are more difficult to develop since the bacterial genome is more complex, with numerous candidate antigens, leading to a lengthy and laborious screening process. Immunoproteomics, using western blotting on protein analyzed with 2DE and LC-MS/MS to isolate immune-reactive proteins and acquire amino acid sequences, followed by recombinant technology to clone the candidate gene, identified eight candidate antigens from Ph.d.p., which have been cloned and expressed in Escherichia coli BL21(DE3). These proteins were purified and used as antigens in an efficacy trial. Three, rHSP60, rENOLASE, and rGAPDH proteins, elicited higher specific antibody titers and stronger protective immunity than the other five and an inactivated Ph.d.p. whole bacterial vaccine. These three antigens may be candidates for the development of a subunit vaccine against Ph.d.p.     

Comparative screening of recombinant antigen thermostability for improved leptospirosis vaccine design

Recombinant antigens exhibit targeted protectiveproperties and offer important opportunities in the development of therapeutic technologies. Biophysical and structural methods have become important tools for the rational design and engineering of improved antigen-based vaccines. Vaccines containing Leptospira immunoglobulin-like (Lig) protein-derived antigens are currently the most promising candidates for protective immunity against the globally prevalent bacterial pathogen, Leptospira interrogans; however, vaccine trials using these domains have produced inconsistent results. Here, we compare the thermostability of domains from the main immunogenic regions from major leptospiral antigens, LigA and LigB. By measuring temperature-dependent fluorescence decay of the hydrophobic core tryptophan, 17 individual Lig protein immunoglobulin-like (Ig-like) domains were shown to display a broad range of unfolding temperatures. For a majority of the domains, stability issues begin to occur at physiologically relevant temperatures. A set of chimeric Ig-like domains was used to establish the ability of transplanted domain regions to enhance thermostability. Further insights into the determinants for domain stabilization were explored with nuclear magnetic resonance dynamics and mutational analysis. The current study has yielded a set of thermostable Ig-like domain scaffolds for use in engineering antigen-based vaccines and demonstrates the importance of incorporating thermostability screening as a design parameter.     

Vaccination-induced systemic autoimmunity in farmed Atlantic salmon

Over half of the salmon consumed globally are farm-raised. The introduction of oil-adjuvanted vaccines into salmon aquaculture made large-scale production feasible by preventing infections. The vaccines that are given i.p. contain oil adjuvant such as mineral oil. However, in rodents, a single i.p. injection of adjuvant hydrocarbon oil induces lupus-like systemic autoimmune syndrome, characterized by autoantibodies, immune complex glomerulonephritis, and arthritis. In the present study, whether the farmed salmon that received oil-adjuvanted vaccine have autoimmune syndrome similar to adjuvant oil-injected rodents was examined. Sera and tissues were collected from vaccinated or unvaccinated Atlantic salmon (experimental, seven farms) and wild salmon. Autoantibodies (immunofluorescence, ELISA, and immunoprecipitation) and IgM levels (ELISA) in sera were measured. Kidneys and livers were examined for pathology. Autoantibodies were common in vaccinated fish vs unvaccinated controls and they reacted with salmon cells/Ags in addition to their reactivity with mammalian Ags. Diffuse nuclear/cytoplasmic staining was common in immunofluorescence but some had more specific patterns. Serum total IgM levels were also increased in vaccinated fish; however, the fold increase of autoantibodies was much more than that of total IgM. Sera from vaccinated fish immunoprecipitated ferritin and approximately 50% also reacted with other unique proteins. Thrombosis and granulomatous inflammation in liver, and immune-complex glomerulonephritis were common in vaccinated fish. Autoimmunity similar to the mouse model of adjuvant oil-induced lupus is common in vaccinated farmed Atlantic salmon. This may have a significant impact on production loss, disease of previously unknown etiology, and future strategies of vaccines and salmon farming.