Towards broad-spectrum protection: the development and challenges of combined respiratory virus vaccines.

In the post-COVID-19 era, the co-circulation of respiratory viruses, including influenza, SARS-CoV-2, and respiratory syncytial virus (RSV), continues to have significant health impacts and presents ongoing public health challenges. Vaccination remains the most effective measure for preventing viral infections. To address the concurrent circulation of these respiratory viruses, extensive efforts have been dedicated to the development of combined vaccines. These vaccines utilize a range of platforms, including mRNA-based vaccines, viral vector vaccines, and subunit vaccines, providing opportunities in addressing multiple pathogens at once. This review delves into the major advancements in the field of combined vaccine research, underscoring the strategic use of various platforms to tackle the simultaneous circulation of respiratory viruses effectively.

Development of novel Streptococcus equi vaccines with an assessment of their immunizing potentials and protective efficacies.

Strangles is a highly contagious disease of the equine upper respiratory tract caused by Streptococcus equi subspecies. Streptococcus equi subsp. equi (S. equi) and Streptococcus equi subsp. zooepidemicus (S. zooepidemicus) was isolated, as local, hot, and field strains, from horses clinically suffering from respiratory distress. The isolated Streptococci were identified using bacteriological and molecular techniques. Four formulations of inactivated S. equi vaccines were developed and evaluated. The first formulation was prepared using the S. equi isolates, adjuvanted with MONTANIDE GEL adjuvant, while the second formulation was adjuvanted with MONTANIDE ISA-70 adjuvant. The other 2 formulations were inactivated combined vaccines prepared from both S. equi and S. zooepidemicus isolates. The 3rd formulation was the combined isolates adjuvanted with MONTANIDE GEL while the 4th formulation was the combined isolates adjuvanted with MONTANIDE ISA-70. The developed vaccines' physical properties, purity, sterility, safety, and potency were ensured. The immunizing efficacy was determined in isogenic BALB/c mice and white New Zealand rabbits using the passive hemagglutination test. Also, the antibodies' titer of the combined S. equi and S. zooepidemicus vaccine adjuvanted with MONTANIDE ISA-70 in foals was tracked using an indirect enzyme-linked immunosorbent assay. The protective efficacy of the developed vaccines was determined using a challenge test in both laboratory and field animal models, where a 75% protection rate was achieved. The combined vaccine proved to be more efficacious than the monovalent vaccine. Also, the MONTANIDE ISA-70 adjuvant provided significant protective efficacy than the MONTANIDE GEL. The current work is introducing a very promising mitigative and strategic controlling solution for strangles.

Immunogenicity and safety of adsorbed diphtheria-purified pertussis-tetanus-inactivated polio (Sabin strain)-Haemophilus type b conjugate combined vaccine (DPT-IPV-Hib) in healthy Japanese Infants ≥ 2 and < 43 months of Age: A phase III, multicenter, active controlled, assessor-blinded, randomized, parallel-group study.

OBJECTIVE: This study investigated the immunogenicity and safety of a pentavalent vaccine Gobik (DPT-IPV-Haemophilus influenzae type b [Hib]) in healthy Japanese infants aged ≥ 2 and < 43 months using a concomitant vaccination with ActHIB® (Hib) and Tetrabik (DPT-IPV) as a comparator. METHODS: This study was conducted as a phase 3, multicenter, active controlled, assessor-blinded, randomized, parallel-group study. Participants received a total of 4 subcutaneous doses (3 primary immunization doses and a booster dose) of either the experimental drug (DPT-IPV-Hib) or the active comparator (Hib + DPT-IPV). The primary endpoints were the anti-PRP antibody prevalence rate with ≥ 1 µg/mL, and the antibody prevalence rates against pertussis, diphtheria toxin, tetanus toxin, and attenuated poliovirus after the primary immunization. RESULTS: In 267 randomized participants (133 in the DPT-IPV-Hib group and 134 in the Hib + DPT-IPV group), the antibody prevalence rates after the primary immunization in both groups were 100.0 % and 88.7 % for anti-PRP antibody with ≥ 1 µg/mL, 99.2 % and 98.5 % against diphtheria toxin, and 100.0 % and 99.2 % against tetanus toxin, respectively. The antibody prevalence rates against pertussis and attenuated poliovirus were 100.0 % in both groups. The non-inferiority of the DPT-IPV-Hib group to the Hib + DPT-IPV group was verified for all measured antibodies. In both groups, all the GMTs of antibodies after the primary immunization were higher than those before the first dose, and those after the booster dose were higher than those after the primary immunization. No safety issues were identified. CONCLUSION: A single-agent Gobik, the first DPT-IPV-Hib pentavalent vaccine approved in Japan, was confirmed to simultaneously provide primary and booster immunizations against Hib infection, pertussis, diphtheria, tetanus, and poliomyelitis and to have a preventive effect and safety comparable to concomitant vaccination with Hib (ActHIB®) and DPT-IPV quadrivalent vaccine (Tetrabik).

Age-specific prevalence of IgG against measles/rubella and the impact of routine and supplementary immunization activities: A multistage random cluster sampling study with mathematical modelling.

BACKGROUND: Vietnam continues to have measles and rubella outbreaks following supplementary immunization activities (SIA) and routine immunization despite both having high reported coverage. To evaluate immunization activities, age-specific immunity against measles and rubella, and the number of averted Congenital Rubella Syndrome (CRS) cases, must be estimated. METHODS: Dried blood spots were collected from 2091 randomly selected individuals aged 1-39 years. Measles and rubella virus-specific immunoglobulin G (IgG) were measured by enzyme immunoassay. Results were considered positive at ≥120 mIU/mL for measles and ≥10 IU/mL for rubella. The number of CRS cases averted by immunization since 2014 were estimated using mathematical modelling. RESULTS: Overall IgG seroprevalence was 99.7% (95%CI: 99.2-99.9) for measles and 83.6% (95%CI: 79.3-87.1) for rubella. Rubella IgG seroprevalence was higher among age groups targeted in the SIA than in non-targeted young adults (95.4% [95%CI: 92.9-97.0] vs 72.4% [95%CI: 63.1-80.1]; P < 0.001). The estimated number of CRS cases averted in 2019 by immunization activities since 2014 ranged from 126 (95%CI: 0-460) to 883 (95%CI: 0-2271) depending on the assumed postvaccination reduction in the force of infection. CONCLUSIONS: The results suggest the SIA was effective, while young adults born before 1998 who remain unprotected for rubella require further vaccination.

Transformative vaccination: A pentavalent shield against COVID-19 and influenza with betulin-based adjuvant for enhanced immunity.

The development of an effective combined vaccine represents a crucial strategy for preventing outbreaks of infectious diseases and reducing the burden on healthcare resources. Developing a combined vaccine against both influenza and the coronavirus is a promising approach, but it is still in the early stages of development. This paper reports on a novel combined pentavalent candidate vaccine that has shown promising results in mice, with statistically significant differences in mean antibody titer against the coronavirus and the influenza antigens compared to placebo. We have shown that the coronavirus antigen is capable of inducing an immune response autonomously, regardless of the presence of the influenza antigens in a combined vaccine. On the other hand, the presence of the coronavirus antigen in a combined vaccine showed to enhance the immune response against some of the studied influenza antigens, suggesting that these antigens may act in synergy and elicit an enhanced immune response. The absence of dose-dependent difference in mean antibody titer within the same antigenic groups of vaccine preparations suggested that even small amounts of the coronavirus and the influenza antigens could induce an immune response just as good as high-dose vaccine preparations, which certainly has important safety and cost implications. The vaccine is soon to be ready for clinical trials and mass production.

Investigation of the Optimal Immunization Dose and Protective Efficacy of an Attenuated and Marker M. bovis-Bovine Herpesvirus Type 1 Combined Vaccine in Rabbits.

Bovine respiratory disease (BRD) is one of the most common diseases in the cattle industry; it is a globally prevalent multifactorial infection primarily caused by viral and bacterial coinfections. In China, Mycoplasma bovis (M. bovis) and bovine herpesvirus type 1 (BoHV-1) are the most notable pathogens associated with BRD. Our previous study attempted to combine the two vaccines and conducted a preliminary investigation of their optimal antigenic ratios. Based on this premise, the research extended its investigation by administering varying vaccine doses in a rabbit model to identify the most effective immunization dosage. After immunization, all rabbits in other immunization dose groups had a normal rectal temperature without obvious clinical symptoms. Furthermore, assays performed on the samples collected from immunized rabbits indicated that there were increased humoral and cellular immunological reactions. Moreover, the histological analysis of the lungs showed that immunized rabbits had more intact lung tissue than their unimmunized counterparts after the challenge. Additionally, there appears to be a positive correlation between the protective efficacy and the immunization dose. In conclusion, the different immunization doses of the attenuated and marker M. bovis HB150 and BoHV-1 gG-/tk- combined vaccine were clinically safe in rabbits; the mix of 2.0 × 108 CFU of M. bovis HB150 and 2.0 × 106 TCID50 BoHV-1 gG-/tk- strain was most promising due to its highest humoral and cellular immune responses and a more complete morphology of the lung tissue compared with others. These findings determined the optimal immunization dose of the attenuated and marker M. bovis HB150 and BoHV-1 gG-/tk- combined vaccine, laying a foundation for its clinical application.

Parents' and healthcare professionals' perception toward the introduction of a new fully liquid hexavalent vaccine in the Malaysian national immunization program: a cross-sectional study instrument development and its application.

A newly developed fully liquid hexavalent vaccine that comprises six antigens for Diphtheria, Tetanus, acellular Pertussis, Inactivated Poliomyelitis, Haemophilus Influenza type b., and Hepatitis B, is proposed to be introduced in the Malaysian national immunization program, instead of the non-fully liquid pentavalent vaccine and monovalent Hepatitis B vaccine that is currently employed in the immunization schedule. Although the introduction of new vaccines is a necessary intervention, it still needs to be accepted by parents and healthcare professionals. Hence, this study aimed to develop three structured questionnaires and to investigate the participants' perception and acceptability toward the incorporation of the new fully liquid hexavalent vaccine. A cross-sectional study was conducted among a sample of 346 parents, 100 nurses, and 50 physicians attending twenty-two primary health care centers in the states of Selangor and the Federal Territory of Kuala Lumpur and Putrajaya during 2019-2020. The study found that Cronbach's alpha coefficients for the study instruments ranged from 0.825 to 0.918. Principal components analysis produced a good fit with KMO>0.6. For the parents' perception questionnaire, the only extracted factor explained 73.9 % of the total variance; for the nurses' perception toward a non-fully and fully liquid combined vaccine, there was a sole extracted factor that explained 65.2 % and 79.2% of the total variance, respectively. Whereas for the physicians' perception, there was one factor extracted that explains 71.8 % of the total variance. The median score for all the questionnaire items ranged from 4 to 5 (Q1 and Q3 vary between 3-5). Parents' ethnicity was significantly associated (P-value ≤ 0.05) with the perception that the new hexavalent vaccine would reduce their transportation expenses. Moreover, a significant association (P-value ≤ 0.05) was found between physicians' age and the perception of the hexavalent vaccine's ability to decrease patient overcrowding in primary healthcare centers. The instruments used in this study were valid and reliable. Parents of Malay ethnicity were the most concerned about transportation expenses since they have the lowest income and are more concentrated in rural areas compared to other races. Younger physicians were concerned about reducing patient crowding and hence reducing their workload and burnout.

Research progress on combined vaccines based on diphtheria-tetanus and acellular pertussis vaccine / 中国生物制品学杂志

@#Combined vaccine is a single vaccine preparation made by mixing two or more different organism or purified antigens by physical methods.The use of combined vaccine can reduce the number of immunization shots and improve the compliance of children and acceptance of parents;reduce the costs of transportation,storage and management;avoid missing vaccination and improve vaccination rate.At present,a variety of combined vaccines have been licensed abroad,which have good safety and immunogenicity;some combined vaccines have been put on the market in China,and many combined vaccines are in clinical trials.In recent years,with the successful development of component pertussis vaccine and inactivated poliovirus vaccines of Sabin strain Ⅰ,Ⅱ and Ⅲ in China,the combined vaccines based on diphtheria-tetanus-acellular pertussis vaccine(DTaP) have been greatly developed.In this paper,the research progress on combined vaccines based on DTaP,which have been licensed and in clinical trials at home and abroad,was reviewed,in order to provide ideas for the development of related combined vaccines in China.

[Quality analysis of a combined domestic vaccine for the prevention of measles, rubella and mumps].

INTRODUCTION: The need to maintain a high level of vaccination coverage against measles, rubella and mumps in conditions of an increased risk of outbreaks of infections due to violations of vaccination tactics associated with the pandemic of coronavirus infection and due to the unfavorable epidemic situation in neighboring countries determines the advisability of using a combined vaccine for the simultaneous prevention of these three socially significant infections. THE AIM OF THE STUDY: to analyze the quality of commercial series of a new domestic combined cultured live vaccine against measles, rubella and mumps (MRM) throughout the entire time of its manufacturing according to all specification indicators in regulatory documentation (RD). MATERIALS AND METHODS: The object of the study was the combined cultured live vaccine against measles, rubella and mumps. The analysis of the quality of the drug was carried out according to 86 consolidated production protocols of manufactured series, as well as according to the results of control of these series in the Testing Center for Quality Expertise of the Federal State Budgetary Institution NCESMP of the Ministry of Health of the Russian Federation. RESULTS: It is shown that the quality of the combined drug for the prevention of measles, rubella and mumps corresponds to the RD in all studied indicators. The drug does not contain an antibiotic. Bovine serum albumin, which is a technological impurity, is detected in quantities more than 5 times lower than the established norm. A comparison of the specific activity of the viral components of new combined domestic vaccine and the components of the bivalent vaccine against measles and mumps produced by the company in 20192021 showed that the spread of the activity values of the viral components in the new drug and in the series of mumps-measles vaccine was minimal, which allowed us to make a conclusion about the stability of the production technology. CONCLUSION: The quality of the new domestic combined vaccine for the prevention of measles, rubella and mumps meets WHO requirements. The results of the conducted studies indicate the stability of production and the standard quality of the drug. The use of a combined vaccine against three significant infections will ensure the necessary level of vaccination coverage in the population. Information about the results of studies can help reduce the number of vaccination refusal.

Theories-based determinants analysis of Hib-combined vaccine hesitancy in China: A multi-group structural equation modeling.

OBJECTIVES: To explore determinants of Hib-combined vaccine hesitancy in Chinese parents, and to provide scientific intervention measures to tackle vaccine hesitancy. METHODS: 2,531 parents were recruited from local healthcare centers in Zhejiang Province by accidental sampling, and completed the self-developed online questionnaire with voluntary participation. Health Belief Model and Model of Determinants of Vaccine Hesitancy were applied to construct the framework of research. Multi-group Structural Equation Modeling was performed to explore the effects of determinants of vaccine hesitancy across various socio-economic status (SES). RESULTS: Hib-combined vaccine hesitancy for total sample was 2.184 ± 0.777 (95%CI: 2.153-2.214), and most of them were in low (n = 1436, 56.7%) level. Low SES group (2.335 ± 0.763, 95%CI: 2.271-2.400) had significantly highest vaccine hesitancy. For total sample, Self-Efficacy and Cues to Action presented -0.517 and -0.437 of standard total effect on Vaccine Hesitancy, respectively. The Multi-group Structural Equation Model with satisfying goodness of fit in SES groups (χ2 = 1616.074, df = 314, χ2/df = 5.147, CFI = 0.973, TLI = 0.966, SRMR = 0.027, RMSEA = 0.041) showed that Cues to Action imposed -0.621 (95%CI: -0.867-0.389, p < .001) of major standard total effect on Vaccine Hesitancy in low SES group, while Self-Efficacy imposed -0.560 (95%CI: -0.668-0.444, p < .001) and -0.685 (95%CI: -0.841-0.454, p < .001) of principal standard total effect on Vaccine Hesitancy in middle and high SES groups, respectively. CONCLUSIONS: Hib-combined vaccine hesitancy in Chinese parents was low, and the lower the SES, the higher the vaccine hesitancy. Cues to Action and Self-Efficacy played primary role in declining vaccine hesitancy for parents at low SES, and at middle and high SES, respectively.

Preparation and evaluation of a new combined conjugated vaccine against Klebsiella pneumonia and Pseudomonas aeruginosa.

AIMS: Lower respiratory tract infections (LRTIs) have been identified by the World Health Organization as the most deadly infectious diseases and a pervasive public health problem, causing increased hospital admissions, mortality and antibiotic use. This study aims to determine the most common and resistant bacteria that cause LRTIs and prepare an appropriate vaccine to reduce and prevent potential future infections. METHODS AND RESULTS: Our survey was conducted by collecting respiratory exudate specimens. The most predominant and resistant types were Klebsiella pneumonia and Pseudomonas aeruginosa. The lipopolysaccharides (LPS) were extracted using a modified hot phenol method to prepare the vaccine. The LPS were then activated and conjugated. The immunogenicity of the prepared singles and combined vaccines was determined through an in vivo assay using BALB/c mice. The prepared vaccine provided high protection against the lethal dose of both bacteria in mice. The combined vaccine shows a significant value in achieving high immunization. CONCLUSION: These findings demonstrate the potential of the bacterial LPS molecules to be used as effective vaccines. SIGNIFICANCE AND IMPACT OF STUDY: Developing an effective single and combined vaccine against P. aeruginosa and K. pneumonia can protect and reduce LRTI incidence.

Immunogenicity and Safety of Childhood Combination Vaccines: A Systematic Review and Meta-Analysis.

Background: Vaccination is considered the most effective and economical measure for controlling infectious diseases. Although combination vaccines are widely used worldwide, whether any of the combination vaccines is superior to each separate vaccine has yet to be established. This systematic review and meta-analysis aimed to summarize the available evidence on the effectiveness and safety of combination vaccines in children. Methods: A systematic search was conducted from database inception to August 20, 2021, in MEDLINE, Embase, Cochrane, and Scopus. Published randomized clinical trials (RCTs) and open-label trials of immunogenicity and safety of combined vaccines were selected. The results of the studies were quantitatively synthesized. Results: Overall, 25 articles met the inclusion criteria and were included in the meta-analysis. The results indicated that the combined diptheria−tetanus−acellular pertussis (DTaP)−hepatitis B virus (HBV)−Haemophilus influenzae type B (Hib) vaccine group had lower levels of anti-tetanus antibodies than the combined DTaP−HBV and separate Hib vaccinations group (SMD = −0.23; 95% CI: −0.42, −0.05; p = 0.013). Meanwhile, the combined DTaP−HBV−inactivated polio virus (IPV)−Hib vaccine group had higher levels of anti-pertussis (PT) and anti-filamentous hemagglutinin (FHA) antibodies than the combined DTaP−IPV−Hib and separate HBV vaccinations group (anti-PT: SMD = 0.60; 95% CI: 0.45, 0.75; p < 0.0001; anti-FHA: SMD = 0.40; 95% CI: 0.01, 0.78; p = 0.042). The levels of anti-pertactin (PRN) antibodies were lower in the combined DTaP−IPV−Hib vaccine group than in the combined DTaP−IPV and separate Hib vaccinations group (SMD = −0.13; 95% CI: −0.27, −0.00; p = 0.047). The individuals injected with the DTaP−HBV−IPV−Hib vaccine had a lower risk of pain and swelling than those injected with the combined DTaP−HBV−IPV and separate Hib vaccines (pain: RR = 0.79; 95% CI: 0.69, 0.91; p = 0.001; swelling: RR = 0.87; 95% CI: 0.78, 0.98; p = 0.020). However, the group that received the DTaP−HBV−IPV−Hib vaccine had a higher risk of fever than the group that received DTaP−HBV−IPV and separate Hib vaccinations (RR = 1.13; 95% CI: 1.02, 1.26; p = 0.021). Conclusions: This meta-analysis suggests that the combined vaccines (DTaP−IPV−Hib, DTaP−HBV−Hib, DTaP−HBV−IPV−Hib) are safe, well-tolerated, and provide immunogenic alternatives to separate vaccines in children. The combined DTaP−HBV−IPV−Hib vaccine showed a higher incidence of fever, which was lower than the cumulative incidence of fever induced by all vaccines. Future studies should evaluate the cost-effectiveness of using combined vaccines and compare the potency of different formulations to improve routine local or national childhood immunization programs.

Surveillance on the adverse events following immunization with the pentavalent vaccine in Zhejiang, China.

OBJECTIVES: The aim of this study is to describe the reporting rate of adverse events following immunization (AEFI) with pentavalent vaccine: diphtheria-pertussis-tetanus-poliomyelitis-Haemophilus influenzae type b (DPT-IPV/Hib), and to determine whether the reporting rate of AEFI following DPT-IPV/Hib was higher than the average level of the other vaccines. METHODS: Review and describe the AEFI reported to national adverse event following immunization surveillance system (NAEFISS) in Zhejiang province from 2015 to 2020. Reporting rates of AEFI were calculated by age, city, severity of AEFI, categories of AEFI, and reaction categories. The data mining algorithm used in this study was reporting odds ratio (ROR). A value of ROR­1.96SE >1 (standard error [SE]) was considered as positive signal. RESULTS: NAEFISS received 5726 AEFI reports following DTP-IPV/Hib, with a reporting rate of 20.01/10000 doses. Of the reported AEFI, 202 were serious vaccine product-related reactions, including two cases of anaphylactic shock, five cases of Guillain Barre Syndrome (GBS) and two cases of acute disseminated encephalomyelitis. The reporting rate of fever/redness/induration was the highest among all the clinical diagnosis (14.97/10000 doses). The positive signals were obtained for allergic rash (ROR-1.96SE: 1.36), febrile convulsion (ROR-1.96SE: 1.32) and GBS (ROR-1.96SE: 1.16). CONCLUSION: The present findings bolstered that the DTP-IPV/Hib administered as the four-dose schedule was generally well tolerated in Chinese infants as we did not identify any new/unexpected safety concern from the NAEFISS during a six-year timespan.

Duration of Protective Immunity in Sheep Vaccinated with a Combined Vaccine against Peste des Petits Ruminants and Sheep Pox.

In this study, the ability of the combined vaccine against peste des petits ruminants (PPR) (Nigeria strain 75/1) and sheep pox (SPP) (NISKhI strain) to form a protective immune response for 12 months in Kazakh breed fine-fleeced sheep aged 6-12 months was demonstrated. The duration of the protective immunity of immunized sheep from PPR and from SPP was evaluated using a serum neutralization test (SNT), followed by testing of the resistance of vaccinated sheep to infection with the field strain Kentau-7 of the PPRV and the virulent strain A of the SPPV. The PPR antibody response was additionally measured by c-ELISA. A single immunization of sheep with a combined vaccine in a volume of 2.0 mL, containing the PPR and SPP vaccine viruses in the titers of 103.0 TCID50/mL, provided reliable protection of animals from two infections simultaneously for 12 months (observation period). At the same time, in sheep immunized with the combined vaccine, antibodies of PPRV persisted for up to 12 months, with slight fluctuations. The combined vaccine induced 100% clinical protection against the field strain of PPRV and the virulent strain of SPPV in immunized sheep for up to 12 months, while unvaccinated animals became ill with the manifestation of clinical signs specific to PPRV and SPPV.

Was Aldo Castellani the inventor of combined and polyvalent vaccines?

Italian born and long term resident in England, Sir Aldo Castellani (1874-1971), is usually credited with "several discoveries of great importance in tropical medicine", most notably for his role in determining the aetiology of sleeping sickness and yaws. This contribution tries to highlight his role in the history of vaccinology as a pioneer in the design and use of combined and polyvalent vaccines. In the light of existing data, while acting as Director of the Bacteriological Institute of Colombo (Ceylon) in the decade before the First World War, Castellani was the first to experiment with both different strains of "antigens belonging to the same group" like in his typhoid-paratyphoid vaccine (TAB), as well as the simultaneous use of more pathogens, or part of them, for protection against different diseases, like in his "tetravaccine" (TAB + cholera) and "pentavaccine" (TAB + cholera + Malta fever). At the beginning of the War, based on the results of thousands of vaccinations, he strongly maintained that those combined or mixed vaccines were harmless and effective. The Allied Armies became more and more interested in Castellani's methods. His TAB vaccine was extensively used among the soldiers and his contributions were largely acknowledged especially in the Anglo-Saxon world in the following years, when it was plainly stated that "to Castellani is due the credit of having first proposed, prepared, and used, combined vaccines". The path to widespread use of combination and polyvalent vaccines - which is usually dated back only to the late 1940s - was still long and winding. Castellani himself abandoned that field of research after the War and this is probably why that early history is nowadays often forgotten.

A novel combined vaccine against classical swine fever and porcine epidemic diarrhea viruses elicits a significant Th2-favored humoral response in mice.

Many Chinese breeding pigs are repeatedly vaccinated against classical swine fever virus (CSFV) and porcine epidemic diarrhea virus (PEDV), which cause fatal, highly contagious diseases. To reduce their high frequency vaccination-induced immune stress, we constructed a combined vaccine based on the E2 protein of CSFV and the S1 spike protein subunit of PEDV (named E2-S1). In mice, the E2-S1 vaccine elicited higher neutralizing antibody titers and IgG1/IgG2a ratios against CSFV and PEDV than those induced by individual E2 or S1 vaccines. Moreover, it elicited high IL-4 expression, but no IFN-γ expression. The results suggest that good compatibility exists between E2 and S1 antigens, and the E2-S1 vaccine can elicit a strong Th2-type cell-mediated humoral immune response. The E2-S1 recombinant fusion protein provides a novel vaccine candidate against both CSFV and PEDV, laying the foundation for future combination vaccines against swine diseases.

Preclinical safety assessment of a combined vaccine against Hepatitis a virus and enterovirus 71.

Since 2007, Hepatitis A (HAV) vaccination has been a part of the National Immunization Program of China. Recognizing enterovirus 71 (EV71) as the most important pathogen in severe hand, foot and mouth disease, an inactivated EV71 vaccine was successfully marketed in 2015. Based on the concept of one vaccine preventing two diseases and owing to similarities in vaccine preparation and the overlap of the eligible population, a combination of the inactivated HAV vaccine and inactivated EV71 vaccine is theoretically feasible and desirable. However, the optimal vaccinationschedule for this combination vaccine has yet to be optimized. Use of this combined vaccine would not only decrease the number of vaccinations, but also lower associated cost. This study aimed to investigate the toxicity and adverse reactions of the combined HAV-EV71 vaccine under Good Laboratory Practice conditions to provide a reference for clinical studies/applications in the future. CD®(Sprague Dawley) IGS rats were employed for single-dose toxicity testing using a high dose, and repeated-dose toxicity testing using high, as well as low doses. Animals that received only a single dose showed no obvious clinical symptoms nor abnormal body weight, and no significant gross pathological change at the experimental endpoint at necropsy. In the rats injected with three doses, phagocytosis of basophilic granules by macrophages was observed in the inguinal, mesenteric, and local lymph nodes, besides irritation at the administration site. At 56 days after the last dose, no significant histopathological change was observed in the lymph nodes, and local irritation gradually faded. Further, systematic allergy testing was performed in guinea pigs. After systemic sensitization and challenge with the HAV-EV71 vaccine, animals showed normal weight gain and no allergic reactions. This study, therefore, confirmed a good safety profile of the inactivated HAV and EV71 combined vaccine.

Efficacy, safety, and formulation issues of the combined vaccines.

Introduction: Controlling the preventable infectious diseases is the main goal of vaccination. Among the vaccines, combined vaccines are of great importance for their social, public health, and economic values. It is stated that the combined vaccines are as efficient and safe as the monovalent vaccines. However, a concern has raised about the efficacy and safety of the combined vaccines due to the outbreaks of vaccine-preventable diseases and occurrence of serious adverse events. Areas covered: A retrospective literature search was conducted in the Google Scholar and PubMed databases to evaluate the efficacy and safety of the combined vaccines from 1980 to 2020 using appropriate keywords. Expert opinion: Several studies have shown efficacy and safety issues related to the combined vaccines. Different factors contribute to the inefficacy and lack of safety in the vaccines including formulation problems, limited data in the pre-licensure studies and challenges related to imperfection of the post-licensure surveillance systems. For surmounting the mentioned obstacles, there is a need to provide new formulations of the vaccines, revise the vaccines҆ safety and efficacy acceptance standards in the pre-licensure studies, improvement of post-licensure surveillance systems, and education of healthcare staff.

Gilt Vaccination with a Mixed Administration of a PRRS MLV and a PPV1 Subunit Vaccine Protects against Heterologous PRRSV1 Infection and Prevents Detrimental Effects on Piglet Performance.

The efficacy of the combined administration of a porcine reproductive and respiratory syndrome (PRRS) modified live virus (MLV) vaccine and a porcine parvovirus 1 (PPV1) subunit vaccine in gilts was addressed in two experiments. Experiment A aimed to establish a 4-week onset of immunity (OOI). Gilts were randomly distributed in three treatment groups: non-vaccinated control animals (group 1), animals vaccinated with the combined vaccine (group 2), and a third group that consisted of animals vaccinated with the PRRS MLV vaccine alone (group 3). Four weeks after the first vaccination, gilts were challenged with a heterologous PRRS virus 1 (PRRSV1) and euthanized three weeks after. Besides this, experiment B pursued a 17-week duration of immunity (DOI). In this case, gilts were distributed in the same treatment groups, but for the third group, which consisted of non-vaccinated, non-challenged animals were used instead. For the DOI assessment, gilts were artificially inseminated 4 weeks after the first vaccination, challenged at day 90 of gestation, and followed up, together with their offspring, until day 20 post-farrowing. Serology and viremia post-challenge were determined in gilts from both experiments, while farrowing and piglet performance were only evaluated in experiment B. Overall, the combined vaccine helped to protect gilts from viremia post-challenge and, consequently, to prevent PRRS clinical symptoms and diminish the proportion of piglets infected congenitally or early in life. The combined vaccine also elicited a significant improvement in piglet survival rate and growth performance until weaning. The present results reveal efficacy and lack of interference of the mixed use of the tested vaccines against PRRSV1 infection, with at least 4-week OOI and 17-week DOI.

[A review of combined immunization: current research situation and its promising future].

Combined immunization consists of combined vaccines (including polyvalent vaccines) and simultaneous administration of vaccines, aiming to reduce unnecessary inoculating times for children, and to broaden immunization coverage and a significant larger group of population would be benefit from the Expanded Program on Immunization. In this review, we have summarized a list of research papers focused on combined immunization. By scrutinizing the safety and effectiveness outcomes of combined immunization, we provide some suggestions about upgrading the current immunization program as well as research and development of new combined vaccines.