The Brazilian Experience on BCG Immunization and the Development of New Vaccines against Tuberculosis

Dengue infection is a zoonotic disease caused by Dengue virus, a single-strand RNA flavivirus. It is transmitted to humans through primarily Aedes aegypti (mosquito) bites. The disease prevalence is higher in tropical zones where there are high humidity and temperature as well as unplanned urbanization. According to the WHO, more than 100 tropical countries are afflicted by Dengue infection, leading to severe economic impact. Brazil is currently a major hotspot of Dengue infection. The number of infected people with dengue virus increased 240% in the first trimester of 2015 compared to the same period last year, surpassing the WHO estimative. In an attempt to stop the infection from spreading, the Brazilian Health Ministry has increased the budget to nearly $50 million to combat the vector. However, the bureaucracy of the Brazilian government has led to slow release of the allocated money to the affected cities and the results have been catastrophic. To make the situation worse, the slow diagnosis and the subsequent delay in starting the treatment has led to increased mortality rates. Currently, the only treatment available for Dengue infection is supportive, which is not very efficient against the most severe cases such as Dengue Hemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS).

Recently, I attended the Modern Vaccines Adjuvants and Delivery Systems conference held in Leiden, The Netherlands (May 18-20, 2015); which highlighted some of the major challenges in the development of efficacious vaccines and their effective delivery for both (re) emerging infectious diseases and endemic Neglected Tropical Diseases (NTDs). These infections include not only the “big three” of Malaria, HIV/AIDS and Tuberculosis, but also Leishmaniasis, Ebola, MERSCOV, helminths and others. Notably, for the “big three” attempts to develop such vaccines have been largely disappointing. Some of the challenges lie with the extreme genetic variability of the pathogens. Most successful vaccines have been against slowly evolving pathogens with a limited number of antigenically different strains that induce immune responses dependent on neutralizing antibodies; a mechanism that is well understood. Also, for most vaccine preventable diseases, natural infections with their pathogens leave the host (temporarily, partially) immune to reinfection or disease with the same (strain of) pathogen. The danger of these pathogens is that they often win the race between their own rapid rate of multiplication and the host response which depends on immune recognition and activation and proliferation of immune cells, specifically-B cells. Once the host mounted an immune response and survived the fight he has won the race. Most of the infections above, however, do not conform to that pattern. In TB, cellular mechanisms are essential for controlling the infection, but do not eliminate it. The pathogens, Mycobacterium tuberculosis (Mtb), reproduce very slowly and disease occurs, if at all (in a minority of infections), months or years after infection. Disease, once cured, does not offer protection against reinfection or disease from reinfection. Speed of immune recognition seems to play no role, as most individuals who develop TB have detectable (by IGRA or TST) immune responses to the pathogens. Rather, it seems, a failure of the cellular effector mechanisms is at fault, and if so the prospects for an effective vaccine that protect against disease are slim. As neutralizing antibodies play no role in protection, also the prospects of conferring protection against (re) infection seem equally poor. Immune mechanisms against malaria and HIV are also complex and poorly understood, and attempts to develop an HIV vaccine have been graphically called “shots in the dark” [1]. The more I learn about vaccines and vaccination, the more I become perplexed, less optimistic, but also fascinated. Despite the stunning recent advances in immunology and medical research why do we still fail, and what are the missing scientific links? Are vaccines for some infections simply impossible, or are we simply not aiming our efforts correctly? Progress seems increasingly difficult, but the rewards of success, therefore so huge. The English physician Edward Jenner developed (or rather discovered) that cowpox offered a relatively safe alternative to the risky practice of variation in 1796 and in 1977 smallpox was eradicated worldwide. On May 8, 1980, the World Health Assembly announced that the world was free of smallpox and recommended that all countries cease vaccination: “The world and all its people have won freedom from smallpox, which was the most devastating disease sweeping in epidemic form through many countries since earliest times, leaving death, blindness and disfigurement in its wake” [2]. Jenner just observed, but knew nothing about viruses, let alone immunology.

The Eastern Mediterranean region has set goals for interrupting indigenous transmission of measles using a strategy developed by the World Health Organization. This strategy includes recommendations for vaccination activities to be achieved and sustained thereby increasing the population’s immunity. Measles epidemiological surveillance systems were developed to monitor illnesses characterized by febrile rash, and to provide effective virus detection and serological surveillance. Elimination is defined as the absence of endemic measles transmission in a defined geographical area (e.g., region or country) for ≥12 months in the presence of a well-performing surveillance system. Oman has committed to these goals.

Measles was a leading cause of infant and child morbidity and mortality in Oman before the introduction of measles vaccine by 1975 and thereafter until 1994. With the introduction of a second dose of measles vaccine in 1994, coverage for first and second doses of measles vaccine increased more than 95% in 1996 and has been sustained at a level greater than >95% since then. A national Measles and Rubella (MR) immunization catch-up campaign targeting children ages 15 months to 18 years was conducted in 1994 that achieved 94% coverage. As a result, the incidence of measles has declined markedly in recent years, to ≤ 1 case per million persons in 2012 and to zero cases in 2013.

Oman has made significant progress toward measles elimination and has met the regional elimination goals. However, new challenges faced by Oman, for instance with increased globalization, has led to issues such as outbreaks from imported cases. Additional challenges still remain with regard to increasing identification and immunization of unvaccinated non-Omani workers and their families.

Our research focused on Avian Influenza Type A-H5N1, specifically on an epidemiological model centered in Puerto Rico. Our main goal is to address the following: first, to determine the potential outbreaks of this disease in Puerto Rico using as a base the location of the poultry industry as a hub, we are interested in the repercussions of the infection among the human-to-human potential interaction. The second goal centers on the possibility of vaccination to mitigate an epidemic among humans. In order to address these goals and future ones, we will construct a mathematical model and use parameters according to two cases; the first is a single population model and the second one is a metapopulation model involving 5 cities in Puerto Rico. Our research will specifically target the spread of this particular disease, to investigate possible alternatives to mitigate the spread using measures of immunization. Our results show that a 30% vaccination regime will eradicate the disease in cities that are immunized.

Schistosomiasis remains one of the highly prevalent and serious helminthiases in the countries of Asia, Africa and Latin America. Despite the accessibility of an effective drug against the fatal parasites, drug-based treatment projects still have certain limitations and it is likely that vaccine and effective diagnostic tools are essential for schistosomiasis control. Despite the several decade vaccine development has witnessed the finding and testing of couple of candidate targets, none have shown satisfactory protection. Upon the coming of genome era, it has revolutionized the study of the drug, vaccine, and immunodiagnosis, and also catalyzed a switch from traditional manual testing to automation operation.

For over 50 years, a safe, effective and inexpensive vaccine has been in use but several challenges continue to hamper universal coverage and the sustained control of measles. Before the year 2000, measles was killing over 700,000 children each year worldwide of which 60% occurred in Sub-Saharan Africa [1]. Epidemiologic reports showed that although an estimated 15.6 million deaths had been prevented by measles vaccination between 2000 and 2013, progress has stalled and previous gains are being reversed [2]. Measles related deaths vary depending upon the average age of infection, the nutritional status of the population, measles coverage, HIV infection, vitamin A deficiency and access to health care [3]. The death rate due to measles is so high in Africa that, on average, a child dies every minute. To make the matter worse, every person with measles has a 90% chance of infecting people with whom they come into close contact, if they are unvaccinated [1]. Yet a single dose of measles vaccine is proven to be 93% effective at preventing disease in vulnerable populations exposed to the virus at a relatively low cost ($1 US dollar). The fact that many lives are still lost to this vaccine-preventable virus remains a key concern for global health.

The important biological molecules such as polysaccharides, proteins, allergens and Pathogen Associated Molecular Patterns (PAMPs) are of nanometer in size. Hence, the size, charge, hydrophobic properties will influence their effects on the immune system by way of specific and varied response. Vaccines play a pivotal role in disease containment and prevention. One of the bottle necks is the vaccine administration system. Earlier vehicles and adjuvant systems pose unwanted reactions due to the nature of delivery system used in the vaccine. Delivery systems are those materials used for the administration of vaccines s in a controlled manner aimed to achieve a therapeutic effect. These systems provide: cell or tissue targeted delivery of the antigen, improved antigen presentation, solubility, sustained release and protection of the prophylactic agent from degradation.

Cancer immunotherapy has now finally made its way and entered a new era, after decades of intensive searching of a cure for the incurable. Current attentions are particularly drawn by the very promising outcomes from a series of experimental and clinical studies recently concluded [1], having tested and verified the “Immune Checkpoint Blockade” working hypothesis initially proposed by Dr. James Allison nearly 20 years ago [2]. The next central question is about how to extend or maximize the therapeutic and survival benefits for greater numbers of patients, and of different cancer types. This may be achieved by further identifications of new target checkpoint inhibitors, emphasizing more on the tumor-specific antigenic signals, and through combination with the therapeutic vaccination approach in particular. Here, by joining in the discussion, I intend to start with direct reference to various basic yet constantly evolving concepts based on which vaccination against neoplasm has been developed along, and now progressing towards.

In Mexico, the strategy used for controlling the Avian Influenza Virus (AIV) involves the use of immunizations through an inactivated emulsion vaccine (H5N2), which protects birds from the disease. It has been shown that the strain used in this vaccine is phylogenetically distant from the strains that are isolated in the field. Therefore, the goal of this study was to prepare and evaluate a polyvalent vaccine with genetically divergent isolates of the low-pathogenicity H5N2 avian influenza virus strains that are prevalent in Mexico. A polyvalent vaccine (Poly-AI) was prepared using five isolates that exhibited phylogenetic divergence from the low-pathogenicity avian influenza H5N2 virus strains found in Mexico. Chickens were immunized with Poly-AI and challenged 28 days post-vaccination with two Low Pathogenic Avian Influenza Virus (LPAIV) isolates contained in the vaccine and one High Pathogenic Influenza Virus (HPAIV). Serology was done at different times and clinical signs were recorded. This is the first study that documents the degree of pathogenicity differences between various isolates that exhibit genetic variation in the nation. The experimental Poly-AI vaccine eliminated the clinical signs of the disease, demonstrated 100% protection against the challenge with a highly pathogenic strain and decreased excretion when challenged with homologous and high virulence strains, which was detected by qRT-PCR.

Autoimmune reactions to vaccinations have been reported since vaccines were introduced into modern medical technology. Here, we discuss the possible underlying mechanisms of autoimmune reactions following vaccinations and review cases of autoimmune diseases that have been correlated with vaccination. Molecular mimicry and bystander activation are reported as possible mechanisms by which vaccines can cause autoimmune reactions. Idiopathic Thrombocytopenia Purpura, Myopericarditis, Primary Ovarian Failure, Systemic Lupus Erythematosus (SLE) and Acute Disseminated Encephalomyelitis (ADEM) are all autoimmune conditions with reported links to vaccinations. Genetic predisposition was a definite risk factor for people experiencing autoimmune conditions following immunization; thus understanding the genome of patients is vital for both the development of future generations of vaccines and personalized medicine. Further study is encouraged into the direct associations between vaccines and autoimmune conditions, and the biological mechanisms behind them.