Application of Transthoracic Echocardiography for Cardiac Safety Evaluation in the Clinical Development Process of Vaccines Against Streptococcus pyogenes.

Superficial infections with Streptococcus pyogenes (Strep A), pharyngitis and impetigo can induce acute rheumatic fever, an autoimmune sequela manifesting mostly with arthritis and rheumatic carditis. Valvular heart damage can persist or advance following repeated episodes of acute rheumatic fever, causing rheumatic heart disease. Acute rheumatic fever and rheumatic heart disease disproportionately affect children and young adults in developing countries and disadvantaged communities in developed countries. People living with rheumatic heart disease are at risk of experiencing potentially fatal complications such as heart failure, bacterial endocarditis or stroke. Transthoracic echocardiography plays a central role in diagnosing both rheumatic carditis and rheumatic heart disease. Despite the obvious medical need, no licensed Strep A vaccines are currently available, as their clinical development process faces several challenges, including concerns for cardiac safety. However, the development of Strep A vaccines has been recently relaunched by many vaccine developers. In this context, a reliable and consistent safety evaluation of Strep A vaccine candidates, including the use of transthoracic echocardiography for detecting cardiac adverse events, could greatly contribute to developing a safe and efficacious product in the near future. Here, we propose a framework for the consistent use of transthoracic echocardiography to proactively detect cardiac safety events in clinical trials of Strep A vaccine candidates.

Throat and skin infections caused by certain types of bacteria, named Streptococcus pyogenes, are frequent worldwide; however, in many children from less developed countries and disadvantaged communities, infections with S. pyogenes lead to a condition called acute rheumatic fever, which usually affects the joints and the heart. Damage to the heart valves may evolve to rheumatic heart disease, a permanent condition with often life-threatening complications. Rheumatic heart disease is an important health problem in places and communities where S. pyogenes infections occur frequently. A vaccine against these bacteria would help lower the number of people with valvular heart disease; however, no such vaccine exists yet. Research on vaccines against S. pyogenes was on hold for almost 30 years because of initial concerns that vaccinated children might develop acute rheumatic fever more frequently. Recently, researchers started working again on vaccines against S. pyogenes, but concerns about the safety of such vaccines persist. Doctors can reliably use echocardiography to diagnose cases of rheumatic carditis (as a sign of acute rheumatic fever) and rheumatic heart disease. Here, we propose a simple approach for the consistent use of echocardiography in clinical research of vaccines against S. pyogenes that will allow the detection of any potential heart-related side effects of the vaccine.

Potential for Maternally Administered Vaccine for Infant Group B Streptococcus.

BACKGROUND: Natural history studies have correlated serotype-specific anti-capsular polysaccharide (CPS) IgG in newborns with a reduced risk of group B streptococcal disease. A hexavalent CPS-cross-reactive material 197 glycoconjugate vaccine (GBS6) is being developed as a maternal vaccine to prevent invasive group B streptococcus in young infants. METHODS: In an ongoing phase 2, placebo-controlled trial involving pregnant women, we assessed the safety and immunogenicity of a single dose of various GBS6 formulations and analyzed maternally transferred anti-CPS antibodies. In a parallel seroepidemiologic study that was conducted in the same population, we assessed serotype-specific anti-CPS IgG concentrations that were associated with a reduced risk of invasive disease among newborns through 89 days of age to define putative protective thresholds. RESULTS: Naturally acquired anti-CPS IgG concentrations were associated with a reduced risk of disease among infants in the seroepidemiologic study. IgG thresholds that were determined to be associated with 75 to 95% reductions in the risk of disease were 0.184 to 0.827 µg per milliliter. No GBS6-associated safety signals were observed among the mothers or infants. The incidence of adverse events and of serious adverse events were similar across the trial groups for both mothers and infants; more local reactions were observed in the groups that received GBS6 containing aluminum phosphate. Among the infants, the most common serious adverse events were minor congenital anomalies (umbilical hernia and congenital dermal melanocytosis). GBS6 induced maternal antibody responses to all serotypes, with maternal-to-infant antibody ratios of approximately 0.4 to 1.3, depending on the dose. The percentage of infants with anti-CPS IgG concentrations above 0.184 µg per milliliter varied according to serotype and formulation, with 57 to 97% of the infants having a seroresponse to the most immunogenic formulation. CONCLUSIONS: GBS6 elicited anti-CPS antibodies against group B streptococcus in pregnant women that were transferred to infants at levels associated with a reduced risk of invasive group B streptococcal disease. (Funded by Pfizer and the Bill and Melinda Gates Foundation; C1091002 ClinicalTrials.gov number, NCT03765073.).

ß-glucan mimics tissue damage signaling and generates a trade-off between head kidney and spleen to activate acquired immunity in vaccinated tilapia (Oreochromis niloticus).

The association of vaccines with immunostimulants such as ß-glucan, promote the production of cytokines, competent immune cells and antibodies. However, differences between ß-glucan types and trials make it difficult to understand ß-glucan's mechanism of action. In this study, three trials were carried out with control and fish fed ß-glucan, the first trial occurred at 15 days; the second trial occurred at 30 days when we associated ß-glucan and vaccine; and the third trial occurred at 15 days post-challenge with Streptococcus agalactiae in tilapia (O. niloticus) in order to investigate immune-related gene expression in the head kidney and spleen using real-time qPCR. We found increases in HSP70, IL-6, IL-1ß, TNF-α, IL-10, Lys and C3 predominantly in the head kidney, except for IgM expression, which prevailed in the spleen, under vaccinated + ß-glucan action. This demonstrates the trade-off presented by the head kidney and spleen after immunostimulation in order to produce acquired immunity, as well as an increase in HSP70 expression in vaccinated + ß-glucan fish. The results suggest that ß-glucan stimulates the immune response through damage-associated molecular patterns (DAMPs) recognition. Therefore, these dynamics of the immune response promote a more robust defense against disease.

Immunogenicity and protective efficacy of a Streptococcus suis vaccine composed of six conserved immunogens.

A vaccine protecting against different Streptococcus suis serotypes is highly needed in porcine practice to improve animal welfare and reduce the use of antibiotics. We hypothesized that immunogens prominently recognized by convalescence sera but significantly less so by sera of susceptible piglets are putative protective antigens. Accordingly, we investigated immunogenicity and protective efficacy of a multicomponent vaccine including six main conserved immunogens, namely SSU0934, SSU1869, SSU0757, SSU1950, SSU1664 and SSU0187. Flow cytometry confirmed surface expression of all six immunogens in S. suis serotypes 2, 9 and 14. Although prime-booster vaccination after weaning resulted in significantly higher specific IgG levels against all six immunogens compared to the placebo-treated group, no significant differences between bacterial survival in blood from either vaccinated or control animals were recorded for serotype 2, 9 and 14 strains. Furthermore, vaccinated piglets were not protected against morbidity elicited through intranasal challenge with S. suis serotype 14. As ~50% of animals in both groups did not develop disease, we investigated putative other correlates of protection. Induction of reactive oxygen species (ROS) in blood granulocytes was not associated with vaccination but correlated with protection as all piglets with >5% ROS survived the challenge. Based on these findings we discuss that the main immunogens of S. suis might actually not be a priori good candidates for protective antigens. On the contrary, expression of immunogens that evoke antibodies that do not mediate killing of this pathogen might constitute an evolutionary advantage conserved in many different S. suis strains.

Streptococcus equi-derived extracellular vesicles as a vaccine candidate against Streptococcus equi infection.

Streptococcus equi subspecies equi is a pathogenic bacterium that causes strangles, a highly contagious respiratory infection in horses and other equines. The limitations of current vaccines against S. equi infection warrants the development of an affordable, safe, and effective vaccine. Because gram-positive extracellular vesicles (EVs) transport various immunogenic antigens, they are attractive vaccine candidates. Here, we purified the EVs of S. equi ATCC 39506 and evaluated them as a vaccine candidate against S. equi infection in mice. As an initial step, comparative proteomic analysis was performed to characterize the functional features of the EVs. Reverse vaccinology and knowledge-based annotations were then used to screen potential vaccine candidates (PVCs) for S. equi ATCC 39506. Finally, 32 PVCs were found to be enriched in the EV fraction, suggesting the usefulness of this fraction as a vaccine. Importantly, a significantly higher survival rate after S. equi infection was detected in mice immunized with S. equi-derived EVs via the intraperitoneal route than in mice immunized with heat-killed bacteria. Of note, immunoprecipitation-mass spectrometry results validated various immunogenic antigens within the EV proteome. In conclusion, our results suggest that S. equi-derived EVs can serve as a vaccine candidate against S. equi infection.

Immunogenicity in Oreochromis niloticus vaccinated with sonicated antigens against streptococcosis.

Streptococcosis causes great economic losses in intensive culture of tilapia. Vaccination is the most effective and safest way to tackle infectious diseases. Thus, this study sought the more effective and safer antigenic fraction after sonication of Streptococcus agalactiae to elaborate a vaccine against streptococcosis in Nile tilapia. For this, twenty-one days after vaccination with different fractions (soluble and insoluble) of S. agalactiae, the fish were challenged with the homologous strain (LD50). Then, samples were taken at zero, 14, 28, 60 and 90 days post-vaccination (DPV, n = 7). Blood and organs (cranial kidney, spleen and liver) were collected from vaccinated and unvaccinated fish. Finally, insoluble fraction vaccine presented the best effect, resulting in a 100% relative percent of survival (RPS) and without clinical manifestations. In view of the results, it was to evaluate the role of the insoluble fraction of the antigen in the protective immunity against streptococcosis. The results indicate that the spleen might be the main organ in the vaccine response in Nile tilapia due to the great morphological and immunological differences in vaccinated fish, evidenced by the greater of melanomacrophage centers (MMC) and IgM + lymphocytes in relation to the non-vaccinated fish. At 60 DPV, it was observed the peak of the protective immunity related to the maximum concentration of proteins, circulating leukocytes, antibody titers in the serum and tissue changes with greater expression of IgM + and MMC number in the spleen and kidney of Oreochromis niloticus. Vaccination with insoluble fraction of S. agalactiae was safe and provided effective protection against streptococcosis with maximum protective response at 60 DPV.

Immune response and protective efficacy of two new adjuvants, Montanide™ ISA 763B VG and Montanide™ GEL02, administered with a Streptococcus agalactiae ghost vaccine in Nile tilapia (Oreochromis niloticus).

Streptococcus agalactiae is one of the most important pathogens infecting tilapia worldwide and causes meningoencephalitis, septicemia and high mortalities with considerable losses. Various types of vaccines have been developed against S. agalactiae infection, such as inactivated vaccines, live attenuated vaccines and subunit vaccines. Bacterial ghosts (BGs) are nonliving, empty cell envelopes and have been reported as novel vaccine candidates. Therefore, the main aims of this study were to develop an S. agalactiae ghost vaccine (SAGV) and to evaluate the immune response and protective effect of SAGV against S. agalactiae with two novel adjuvants, Montanide™ ISA 763B VG and Montanide™ GEL02. Nile tilapia, mean weight 50 g, were divided into four groups as follows; 1) fish injected with PBS as control, 2) fish injected with the SAGV alone; 3) fish injected with the SAGV+Montanide™ ISA 763B VG; and 4) fish injected with SAGV+Montanide™ GEL02. Following vaccination, innate immunity parameters including serum lysozyme, myeloperoxidase, catalase, and bactericidal activity were all significantly enhanced. Moreover, specific serum IgM antibodies were induced and reached their highest level 2-8 weeks post vaccination. Importantly, the relative percent survival of tilapia vaccinated against the SAGV formulated with both adjuvants was 80-93%. Furthermore, the transcription of immune-related genes (IgM, TCRß, IL-1ß, IL-8 and TNFα) were up-regulated in tilapia after vaccination, indicating that both cellular and humoral immune responses were induced by these adjuvanted vaccines. In summary, Montanide™ ISA 763B VG and Montanide™ GEL02 can enhance immunoprotection induced by the SAGV vaccine against streptococcosis, demonstrating that both have value as potential adjuvants of fish vaccines.

Prime-Pull Immunization with a Bivalent M-Protein and Spy-CEP Peptide Vaccine Adjuvanted with CAF®01 Liposomes Induces Both Mucosal and Peripheral Protection from covR/S Mutant Streptococcus pyogenes.

Infections with Streptococcus pyogenes and their sequelae are responsible for an estimated 18 million cases of serious disease with >700 million new primary cases and 500,000 deaths per year. Despite the burden of disease, there is currently no vaccine available for this organism. Here, we define a combination vaccine P*17/K4S2 comprising of 20-mer B-cell peptide epitopes, p*17 (a mutant derived from the highly conserved C3-repeat region of the M-protein), and K4S2 (derived from the streptococcal anti-neutrophil factor, Spy-CEP). The peptides are chemically conjugated to either diphtheria toxoid (DT) or a nontoxic mutant form of diphtheria toxin, CRM197. We demonstrate that a prime-pull immunization regimen involving two intramuscular inoculations with P*17/K4S2 adjuvanted with a two-component liposomal adjuvant system (CAF01; developed by Statens Serum Institut [SSI], Denmark), followed by an intranasal inoculation of unadjuvanted vaccine (in Tris) induces peptide- and S. pyogenes-binding antibodies and protects from mucosal and skin infection with hypervirulent covR/S mutant organisms. Prior vaccination with DT does not diminish the response to the conjugate peptide vaccines. Detailed Good Laboratory Practice (GLP) toxicological evaluation in male and female rats did not reveal any gross or histopathological adverse effects.IMPORTANCE A vaccine to control S. pyogenes infection is desperately warranted. S. pyogenes colonizes the upper respiratory tract (URT) and skin, from where it can progress to invasive and immune-mediated diseases. Global mortality estimates for S. pyogenes-associated diseases exceeds 500,000 deaths per year. S. pyogenes utilizes antigenic variation as a defense mechanism to circumvent host immune responses and thus a successful vaccine needs to provide strain-transcending and multicompartment (mucosal and skin) immunity. By defining highly conserved and protective epitopes from two critical virulence factors (M-protein and Spy-CEP) and combining them with a potent immunostimulant, CAF®01, we are addressing an unmet clinical need for a mucosally and skin-active subunit vaccine. We demonstrate that prime-pull immunization (2× intramuscular injections followed by intranasal immunization) promotes high sustained antibody levels in the airway mucosa and serum and protects against URT and invasive disease.

Preclinical safety and immunogenicity of Streptococcus pyogenes (Strep A) peptide vaccines.

We have developed two candidate vaccines to protect against multiple strains of Strep A infections. The candidates are combinatorial synthetic peptide vaccines composed of a M protein epitope (J8 or p*17) and a non-M protein epitope (K4S2). To enhance immunogenicity, each peptide is conjugated to the carrier protein CRM197 (CRM) and formulated with aluminium hydroxide adjuvant Alhydrogel (Alum) to make the final vaccines, J8-CRM + K4S2-CRM/Alum and p*17-CRM + K4S2-CRM/Alum. The safety and toxicity of each vaccine was assessed. Sprague Dawley rats were administered three intramuscular doses, over a six-week study with a 4-week recovery period. A control group received CRM only formulated with Alum (CRM/Alum). There was no evidence of systemic toxicity in the rats administered either vaccine. There was an associated increase in white blood cell, lymphocyte and monocyte counts, increased adrenal gland weights, adrenocortical hypertrophy, and increased severity of granulomatous inflammation at the sites of injection and the associated inguinal lymph nodes. These changes were considered non-adverse. All rats administered vaccine developed a robust and sustained immunological response. The absence of clinical toxicity and the development of an immunological response in the rats suggests that the vaccines are safe for use in a phase 1 clinical trial in healthy humans.

Immunogenicity and protective ability of RpoE against Streptococcus suis serotype 2.

AIMS: RpoE is quite immunogenic and can be used as a candidate vaccine for Streptococcus suis infection via immunoproteomics as reported in our previous studies. In this study, we aimed to verify the immunogenicity of recombinant RpoE and its protective effect against of S. suis. METHODS AND RESULTS: The RpoE protein was successfully expressed in Escherichia coli, and the purified recombinant protein was mixed with ISA206 to prepare an S. suis subunit vaccine. Mice were immunized with the RpoE subunit vaccine and then infected with the virulent S. suis strain ZY05719. Subunit vaccine-immunized mice achieved 50% protection, less pathological damage and less bacterial distribution in each organ compared with the control mice. Furthermore, in vitro culture, showed that mouse antisera significantly (P ï¼œ 0·001) inhibited the growth of S. suis, and qRT-PCR results showed that RpoE successfully induced the up-regulation of IL-6 and TNF-α cytokines. CONCLUSIONS: RpoE mice were vaccinated to obtain immune protection, which may be candidates for S. suis subunit vaccine. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this study will provide new ideas for the development of safe and effective recombinant subunits vaccines for S. suis.

Cross-serotype protection against group A Streptococcal infections induced by immunization with SPy_2191.

Group A Streptococcus (GAS) infection causes a range of diseases, but vaccine development is hampered by the high number of serotypes. Here, using reverse vaccinology the authors identify SPy_2191 as a cross-protective vaccine candidate. From 18 initially identified surface proteins, only SPy_2191 is conserved, surface-exposed and inhibits both GAS adhesion and invasion. SPy_2191 immunization in mice generates bactericidal antibodies resulting in opsonophagocytic killing of prevalent and invasive GAS serotypes of different geographical regions, including M1 and M49 (India), M3.1 (Israel), M1 (UK) and M1 (USA). Resident splenocytes show higher interferon-γ and tumor necrosis factor-α secretion upon antigen re-stimulation, suggesting activation of cell-mediated immunity. SPy_2191 immunization significantly reduces streptococcal load in the organs and confers ~76-92% protection upon challenge with invasive GAS serotypes. Further, it significantly suppresses GAS pharyngeal colonization in mice mucosal infection model. Our findings suggest that SPy_2191 can act as a universal vaccine candidate against GAS infections.

Vaccine-Induced Th1-Type Response Protects against Invasive Group A Streptococcus Infection in the Absence of Opsonizing Antibodies.

Recent global advocacy efforts have highlighted the importance of development of a vaccine against group A Streptococcus (GAS). Combo5 is a non-M protein-based vaccine that provides protection against GAS skin infection in mice and reduces the severity of pharyngitis in nonhuman primates. However, Combo5 with the addition of aluminum hydroxide (alum) as an adjuvant failed to protect against invasive GAS infection of mice. Here, we show that formulation of Combo5 with adjuvants containing saponin QS21 significantly improves protective efficacy, even though all 7 adjuvants tested generated high antigen-specific IgG antibody titers, including alum. Detailed characterization of Combo5 formulated with SMQ adjuvant, a squalene-in-water emulsion containing a TLR4 agonist and QS21, showed significant differences from the results obtained with alum in IgG subclasses generated following immunization, with an absence of GAS opsonizing antibodies. SMQ, but not alum, generated strong interleukin-6 (IL-6), gamma interferon (IFN-γ), and tumor necrosis alpha (TNF-α) responses. This work highlights the importance of adjuvant selection for non-M protein-based GAS vaccines to optimize immune responses and protective efficacy.IMPORTANCE Availability of a group A Streptococcus vaccine remains an unmet public health need. Here, we tested different adjuvant formulations to improve the protective efficacy of non-M protein vaccine Combo5 in an invasive disease model. We show that novel adjuvants can dramatically shape the type of immune response developed following immunization with Combo5 and significantly improve protection. In addition, protection afforded by Combo5 is not mediated by opsonizing antibodies, believed to be the main correlate of protection against GAS infections. Overall, this report highlights the importance of adjuvant selection in raising protective immune responses against GAS invasive infection. Adjuvants that can provide a more balanced Th1/Th2-type response may be required to optimize protection of GAS vaccines, particularly those based on non-M protein antigens.

Structure-based glycoconjugate vaccine design: The example of Group B Streptococcus type III capsular polysaccharide.

Microbial surface polysaccharides are important virulence factors and targets for vaccine development. Glycoconjugate vaccines, obtained by covalently linking carbohydrates and proteins, are well established tools for prevention of bacterial infections. Elucidation of the minimal portion involved in the interactions with functional antibodies is of utmost importance for the understanding of their mechanism of induction of protective immune responses and the design of synthetic glycan based vaccines. Typically, this is achieved by combination of different techniques, which include ELISA, glycoarray, Surface Plasmon Resonance in conjunction with approaches for mapping at atomic level the position involved in binding, such as Saturation Transfer NMR and X-ray crystallography. This review provides an overview of the structural studies performed to map glycan epitopes (glycotopes), with focus on the highly complex structure of Group B Streptococcus type III (GBSIII) capsular polysaccharide. Furthermore, it describes the rational process followed to translate the obtained information into the design of a protective glycoconjugate vaccine based on a well-defined synthetic glycan epitope.

Cross-immunity in Nile tilapia vaccinated with Streptococcus agalactiae and Streptococcus iniae vaccines.

Streptococcus agalactiae and Streptococcus iniae are major bacterial pathogens of tilapia that can cause high mortality concomitant with large economic losses to aquaculture. Although development of vaccines using formalin-killed bacteria to control these diseases has been attempted, the mechanism of immunity against streptococcal infections and the cross-protective ability of these two bacteria remains unclear. To explore the immunological role of these vaccines, we compared the immune responses of tilapia after immunization with both vaccines and compared the relative percent survival (RPS) and cross-immunization protection of tilapia after separate infection with S. agalactiae and S. iniae. All results revealed that vaccinated fish had significantly higher (P < 0.05) levels of specific antibodies than control fish 14 days post secondary vaccination (PSV) and 7 days post challenge. In vaccinated fish, the mRNA expression of interleukin-8 (IL-8), interleukin-12 (IL-12), caspase-3 (C-3), tumour necrosis factor (TNF), and interferon (IFN) was significantly up regulated (P < 0.05) in the head kidney after immunized; similar results were found for IL-8, TNF and IFN in the posterior kidney, meanwhile the expression levels of C-3 and IFN were significantly increased (P < 0.05) in the spleen of vaccinated fish. Additionally, the levels of acid phosphatase (ACP), alkaline phosphatase (AKP), superoxide dismutase (SOD), and lysozyme (LZM) in vaccinated fish were improved at different degree when compared to the control fish. These results showed that vaccination with formalin-killed cells (FKCs) of either S. agalactiae or S. iniae conferred protection against infection by the corresponding pathogen in Nile tilapia, resulting in RPS values of 92.3% and 91.7%, respectively. Furthermore, cross-protection was observed, as the S. agalactiae FKC vaccine protected fish from S. iniae infection, and vice versa. These results suggested that the S. agalactiae and S. iniae FKC vaccines can induce immune responses and generate excellent protective effects in Nile tilapia.

An effective live attenuated vaccine against Streptococcus agalactiae infection in farmed Nile tilapia (Oreochromis niloticus).

Streptococcus agalactiae is an important pathogen associated with various aquatic animals, especially tilapia. Streptococcosis has greatly limited the healthy development of tilapia aquaculture in recent times. The development of novel effective vaccines is important for the prevention and control of streptococcosis in fish. We previously constructed a non-encapsulated S. agalactiae strain △cps by the in-frame deletion method. Here, we evaluated whether this mutant △cps is safe for tilapia and suitable for protection against streptococcosis. We observed that the △cps strain was non-pathogenic to tilapia, and there was no reversion of virulence when it was passaged in tilapia. Moreover, the △cps strain survived for at least 11 d in the main immune organs of tilapia. The tilapia vaccinated via intraperitoneal (IP) injection with △cps strain induced a high antibody titer, and the IgM antibody levels were significantly higher in the vaccinated group than in the control group. The vaccination protected tilapia against the S. agalactiae challenge with a relative percent survival of 90.47%. In addition, tilapia immunized with the △cps strain showed significantly higher expression level of IFN-γ, IL-1ß, MyD88, IgM, and MHC-Iα in the head kidney than those in the control during the entire observation period. The expression of MHC-IIß was inhibited during 1-7 d of immunization. These results revealed that the △cps strain is able to induce humoral and cell-mediated immune response in tilapia. Therefore, the strain △cps has a broad application prospect as a target for attenuation in vaccine development.

[Update on vaccines: 2018 recommendations]. / Actualización sobre vacunas: recomendaciones de 2018.

Beginning in 1974, the date on which the Expanded Program on Immunization was established in the Americas, the number of deaths and disabilities due to certain infectious diseases decreased considerably thanks to universally applied vaccines. A program that initially included four vaccines that protected against six diseases (tuberculosis, diphtheria, pertussis, tetanus, polio and measles) was consolidated, over the years, by incorporating new vaccines and significantly raising coverage rates. The Sociedad Argentina de Pediatría (Argentine Society of Pediatrics), as a leader of opinion, played a leading role in the incorporation of new vaccines, currently reaching one of the most complete vaccination calendars in the world, which improves the levels of inequality and inequity in public health. Taking into account the significant role of the pediatrician in decision-making, the National Committee of Infectious Diseases, together with the Subsidiary Committees, prepared a document on updates and recommendations for 2018 on Polio, Rotavirus, Pneumococcus, Meningococcus, Human Papillomavirus, Chickenpox, Flu, Dengue vaccines and Whooping Cough.

A partir del año 1974, cuando se estableció el Programa Ampliado de Inmunizaciones en las Américas, la cantidad de muertes y discapacidades por enfermedades infecciosas disminuyó de manera considerable gracias a las vacunas aplicadas. Inicialmente, se incluyeron cuatro vacunas que protegían contra seis enfermedades (tuberculosis, difteria, coqueluche, tétanos, polio y sarampión), y, a través de los años, al incorporar nuevas vacunas, aumentaron considerablemente las tasas de cobertura. La Sociedad Argentina de Pediatría tuvo un rol destacado en la incorporación de nuevas vacunas y, en la actualidad, hay uno de los calendarios de vacunación más completos del mundo, lo que permite mejorar los niveles de desigualdad e inequidad en salud pública. Teniendo en cuenta el rol que tiene el pediatra en la toma de decisiones, el Comité Nacional de Infectología, junto con comités de filiales, elaboró un documento sobre actualizaciones y recomendaciones de 2018 acerca de polio, rotavirus, neumococo, meningococo, virus del papiloma humano, varicela, gripe, dengue y coqueluche.

Developing a serocorrelate of protection against invasive group B streptococcus disease in pregnant women: a feasibility study.

BACKGROUND: Group B streptococcus is the leading cause of infection in infants. Currently, intrapartum antibiotic prophylaxis is the major strategy to prevent invasive group B streptococcus disease. However, intrapartum antibiotic prophylaxis does not prevent maternal sepsis, premature births, stillbirths or late-onset disease. Maternal vaccination may offer an alternative strategy. Multivalent polysaccharide protein conjugate vaccine development is under way and a serocorrelate of protection is needed to expedite vaccine licensure. OBJECTIVES: The ultimate aim of this work is to determine the correlate of protection against the major group B streptococcus disease-causing serotypes in infants in the UK. The aim of this feasibility study is to test key operational aspects of the study design. DESIGN: Prospective cohort study of pregnant women and their infants in a 6-month period (1 July to 31 December 2018). SETTING: Five secondary and tertiary hospitals from London and South England. National iGBS disease surveillance was conducted in all trusts in England and Wales. PARTICIPANTS: Pregnant women aged ≥ 18 years who were delivering at one of the selected hospitals and who provided consent during the study period. There were no exclusion criteria. INTERVENTIONS: No interventions were performed. MAIN OUTCOME MEASURES: (1) To test the feasibility of collecting serum at delivery from a large cohort of pregnant women. (2) To test the key operational aspects for a proposed large serocorrelates study. (3) To test the feasibility of collecting samples from those with invasive group B streptococcus. RESULTS: A total of 1823 women were recruited during the study period. Overall, 85% of serum samples were collected at three sites collecting only cord blood. At the two sites collecting maternal, cord and infant blood samples, the collection rate was 60%. A total of 614 women were screened for group B streptococcus with a colonisation rate of 22% (serotype distribution: 30% III, 25% Ia, 16% II, 14% Ib, 14% V and 1% IV). A blood sample was collected from 34 infants who were born to colonised women. Maternal and infant blood and the bacterial isolates for 15 newborns who developed invasive group B streptococcal disease during the study period were collected (serotype distribution: 29% III, 29% II, 21% Ia, 7% Ib, 7% IV and 7% V). LIMITATIONS: Recruitment and sample collection were dependent on the presence of research midwives rather than the whole clinical team. In addition, individualised consent limited the number of women who could be approached each day, and site set-up for the national surveillance study and the limited time period of this feasibility study limited recruitment of all eligible participants. CONCLUSIONS: We have verified the feasibility of collecting and processing rectovaginal swabs and blood samples in pregnant women, as well as samples from those with invasive group B streptococcal disease. We have made recommendations for the recruitment of cases within the proposed GBS3 study and for controls both within GBS3 and as an extension of this feasibility study. FUTURE WORK: A large case-control study comparing specific immunoglobulin G levels in mothers whose infants develop invasive group B streptococcal disease with those in colonised mothers whose infants do not develop invasive group B streptococcal disease is recommended. TRIAL REGISTRATION: Current Controlled Trials ISRCTN49326091; IRAS project identification number 246149/REC reference number 18/WM/0147. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 67. See the NIHR Journals Library website for further project information.

Group B streptococcus is often carried by healthy women and usually causes no problems. Group B streptococcus may be passed from mother to child, primarily through the birth canal, and, in rare cases, can cause serious disease (i.e. pneumonia, sepsis or meningitis) and even death in babies. It may be possible to prevent group B streptococcus disease in babies by giving a vaccine to pregnant women. The reason for vaccinating the mother is so that she can pass on protection (antibodies) during the pregnancy to her baby. A vaccine is currently being developed against group B streptococcus that aims to boost this protection. To help vaccine development progress faster, we need to find out how much antibody is actually needed to protect babies from group B streptococcus disease. A large study is needed to address this question; therefore, we have performed a feasibility study to assess the practicalities of performing this large study. Specifically, we will assess (1) women's willingness to participate in a swabbing and cord blood study, (2) the ability to collect swabs and cord blood once recruited, (3) the ability to identify group B streptococcus disease in this population and (4) the laboratory processing of samples. We recruited 1823 pregnant women from five maternity units in England in a 6-month period: 22% of all women delivering at all sites and 74% of those women who were approached. In three hospitals, cord blood samples from 85% of 1201 women were collected. In two hospitals, we collected 60% of maternal blood samples, 53% of cord blood samples and 99% of swabs from the vagina and rectum from 622 women. A total of 22% of these women carried group B streptococcus in their vagina or gut and we collected blood samples from 34 healthy babies born to these women. During the study, we collected samples from 15 babies who had developed severe group B streptococcus disease; four babies were born to women participating in the study and the rest were identified through national surveillance. In conclusion, we have verified the feasibility of collecting and processing swabs from the vagina and rectum and blood samples in pregnant women, as well as samples from babies who developed group B streptococcus disease. In addition, we have identified a number of strategies that could be adopted in a future study in order to increase recruitment and sample collection.

A Multicomponent Vaccine Provides Immunity against Local and Systemic Infections by Group A Streptococcus across Serotypes.

Group A streptococcus (GAS) species are responsible for a broad spectrum of human diseases, ranging from superficial to invasive infections, and are associated with autoimmune disorders. There is no commercial vaccine against GAS. The clinical manifestations of GAS infection may be attributable to the large repertoire of virulence factors used selectively in different types of GAS disease. Here, we selected five molecules, highly conserved among GAS serotypes, and involved in different pathogenic mechanisms, as a multicomponent vaccine, 5CP. Intranasal (i.n.) immunization with 5CP protected mice against both mucosal and systemic GAS infection across serotypes; the protection lasted at least 6 months. Immunization of mice with 5CP constrained skin lesion development and accelerated lesion recovery. Flow cytometry and enzyme-linked immunosorbent assay analyses revealed that 5CP induced Th17 and antibody responses locally and systemically; however, the Th17 response induced by 5CP resolved more quickly than that to GAS when challenge bacteria were cleared, suggesting that 5CP is less likely to cause autoimmune responses. These findings support that immunization through the i.n. route targeting multiple nonredundant virulence factors can induce immunity against different types of GAS disease and represents an alternative strategy for GAS vaccine development, with favorable efficacy, coverage, duration, and safety.IMPORTANCE GAS is among the most common human pathogens and causes a wide variety of diseases, likely more than any other microorganism. The diverse clinical manifestations of GAS may be attributable to its large repertoire of virulence factors that are selectively and synergistically involved in streptococcal pathogenesis. To date, GAS vaccines have not been successful due to multiple serotypes and postinfection sequelae associated with autoimmunity. In this study, five conserved virulence factors that are involved in GAS pathogenesis were used as a combined vaccine. Intranasal immunization with this vaccine induced humoral and cellular immune responses across GAS serotypes and protected against mucosal, systemic, and skin infections. The significance of this work is to demonstrate that the efficacy of GAS vaccines can be achieved by including multiple nonredundant critical virulence factors and inducing local and systemic immunity. The strategy also provides valuable insights for vaccine development against other pathogens.

Reacciones adversas asociadas a la vacunación en pacientes inmunodeprimidos y en situaciones especiales de una Unidad de Vacunas hospitalaria / Vaccine-related adverse reactions in immunocompromised patients and in special situations of a hospital Vaccine Unit

OBJETIVOS: Describir el tipo de vacunas administradas en la Unidad de Vacunas de un hospital de referencia y calcular la tasa de notificación global y específica de las reacciones adversas asociadas. MÉTODOS: Estudio observacional retrospectivo, realizado en el periodo entre noviembre de 2014 y noviembre de 2017, de los pacientes que desarrollaron una reacción adversa a medicamento (RAM) tras la administración de una vacuna y que fue notificada al Sistema Español de Farmacovigilancia. Las variables analizadas fueron edad, sexo, grupo de riesgo, tipo de vacuna, coadministración y tipo de RAM. Se llevó a cabo un análisis univariante y bivariante. Se calculó la tasa de notificación de RAM global y específica para cada vacuna. RESULTADOS: Se administraron un total de 18.123 vacunas de las que el 20,7% correspondían a la vacuna frente al virus de la hepatitis B. Se notificaron 53 sospechas de RAM. En el 64,2% de las ocasiones se había administrado solamente una vacuna. El 88,7% de las notificaciones correspondieron a vacunas inactivadas. La vacuna frente neumococo polisacárida de 23 serotipos fue la que generó el mayor número de notificaciones. La tasa de notificación global de RAM fue de 0,42%. La vacuna hexavalente fue la que registró la tasa de notificación más elevada (2,81%). El 49,1% de las RAM fueron de tipo sistémico. CONCLUSIONES: La tasa de notificación global fue baja aunque superior a la registrada por otros autores. La correcta notificación de posibles reacciones adversas postvacunales es imprescindible para contribuir a la seguridad vacunal y para aumentar la confianza de la población en las vacunas

OBJECTIVES: The aim of the study was to describe the type of vaccines administered in the Vaccine Unit at a reference hospital. Calculate the overall and specific reporting rate of adverse reactions. METHODS: Retrospective observational study for the period between November 2014 and November 2017, on patients who developed an adverse drug reaction (ADR) after the administration of a vaccine and who were notified to the Spanish Pharmacovigilance System. The variables analyzed were age, sex, risk group, vaccine class, co-administration and type of ADR. A univariate and bivariate analysis was performed. The global and vaccine specific rate of ADR notification was calculated. RESULTS: A total of 18,123 vaccines were administered, of which 20.7% corresponded to hepatitis B virus vaccine. Fifty-three RAM suspects were reported. In 64.2% of cases only one vaccine was administered. Inactivated vaccines accounted for 88.7% of notifications. The highest number of notifications was generated by the 23 serotypes pneumococcal polysaccharide vaccine. The overall reporting rate was 0.42%. The hexavalent vaccine had the highest reporting rate (2.81%).49.1% of the ADR were systemic. CONCLUSIONS: The overall reporting rate was low but higher than that of other authors. Proper reporting of possible adverse post-vaccine reactions is essential to contribute to vaccine safety and to increase public confidence in vaccines

[Vaccine-related adverse reactions in immunocompromised patients and in special situations of a hospital Vaccine Unit]. / Reacciones adversas asociadas a la vacunación en pacientes inmunodeprimidos y en situaciones especiales de una Unidad de Vacunas hospitalaria.

OBJECTIVE: The aim of the study was to describe the type of vaccines administered in the Vaccine Unit at a reference hospital. Calculate the overall and specific reporting rate of adverse reactions. METHODS: Retrospective observational study for the period between November 2014 and November 2017, on patients who developed an adverse drug reaction (ADR) after the administration of a vaccine and who were notified to the Spanish Pharmacovigilance System. The variables analyzed were age, sex, risk group, vaccine class, co-administration and type of ADR. A univariate and bivariate analysis was performed. The global and vaccine specific rate of ADR notification was calculated. RESULTS: A total of 18,123 vaccines were administered, of which 20.7% corresponded to hepatitis B virus vaccine. Fifty-three RAM suspects were reported. In 64.2% of cases only one vaccine was administered. Inactivated vaccines accounted for 88.7% of notifications. The highest number of notifications was generated by the 23 serotypes pneumococcal polysaccharide vaccine. The overall reporting rate was 0.42%. The hexavalent vaccine had the highest reporting rate (2.81%). 49.1% of the ADR were systemic. CONCLUSIONS: The overall reporting rate was low but higher than that of other authors. Proper reporting of possible adverse post-vaccine reactions is essential to contribute to vaccine safety and to increase public confidence in vaccines.