Evaluation of the Safety and Immunogenicity of M-M-RII (Combination Measles-mumps-rubella Vaccine): Clinical Trials of Healthy Children and Adults Published Between 2010 and 2019.

BACKGROUND: The safety and immunogenicity of M-M-RII (measles, mumps and rubella virus vaccine live, Merck & Co., Inc., West Point, PA)-the only combined measles, mumps and rubella vaccine licensed for use in the United States-were previously reported in pre- and postlicensure clinical trials conducted from 1988 to 2009. M-M-RII continues to be evaluated as a comparator in clinical trials of other vaccines. Here, we review safety and efficacy data from more recent clinical trials of M-M-RII. METHODS: We performed a systematic literature review of trials using M-M-RII published from 2010 to 2019. RESULTS: In the 15 studies that met the inclusion criteria, a total of 12,032 subjects were vaccinated: 7667 persons received a first dose only, 2137 participated in 2-dose studies (128 received 1 dose and 2009 received both) and 2063 received a single dose of M-M-RII as their second dose. Dose number was not specified for 165 participants, ≥6 years old, in 2 studies in which a single dose of M-M-RII was administered. Similar to previous reports, M-M-RII was well tolerated and immunogenic when administered alone or concomitantly with other routinely recommended vaccinations. The most common adverse events included transient injection site pain and fever. Serious adverse events were extremely rare, with only 4 probable or potential vaccine-related events reported among the 12,032 participating subjects. CONCLUSIONS: In trials published from 2010 to 2019, M-M-RII continued to be safe and immunogenic in all age groups studied. These data, along with the results of earlier trials, indicate that the performance of the vaccine has been consistent across more than 30 years of postlicensure studies.

Construction of a bivalent vaccine against anthrax and smallpox using the attenuated vaccinia virus KVAC103.

BACKGROUND: Anthrax and smallpox are high-risk infectious diseases, and considered as potential agents for bioterrorism. To develop an effective countermeasure for these diseases, we constructed a bivalent vaccine against both anthrax and smallpox by integrating a gene encoding protective antigen (PA) of Bacillus anthracis to the genome of the attenuated vaccinia virus strain, KVAC103. RESULTS: Immunization with this bivalent vaccine induced antibodies against both PA and vaccinia virus in a mouse model. We also observed that the efficacy of this vaccine can be enhanced by combined immunization with immunoadjuvant-expressing KVAC103. Mouse groups co-immunized with PA-expressing KVAC103 and either interleukin-15 (IL-15) or cholera toxin subunit A (CTA1)-expressing KVAC103 showed increased anti-PA IgG titer and survival rate against B. anthracis spore challenge compared to the group immunized with PA-expressing KVAC103 alone. CONCLUSIONS: We demonstrated that the attenuated smallpox vaccine KVAC103 is an available platform for a multivalent vaccine and co-immunization of immunoadjuvants can improve vaccine performance.

Efficacy of commercial polyvalent avian infectious bronchitis vaccines against Chinese QX-like and TW-like strain via different vaccination strategies.

The infectious bronchitis virus (IBV) is an acute and highly contagious disease, which affects chickens of all ages. Vaccination is the most important way to control this disease. Nevertheless, novel variant strains are constantly reported because of the lack of proofreading capabilities of RNA polymerase and high frequency of homologous RNA recombination. Cross-protection studies has demonstrated that the vaccines could provide great protective effects against viruses of same serotype or genotype. However, the protective effect of different commercial vaccines and vaccine combinations against the prevalent IBV strains in China has rarely been studied. Owing to the multiple genotype or serotype IBV strains prevalence in China, the polyvalent vaccines and their composition were used to expanding the protection spectrum of vaccine in practical application. To evaluate the protection of Chinese commercial IBV polyvalent vaccines against prevalent strains (QX-like and TW I-like), an immune challenge test was conducted. Four polyvalent vaccines, containing 4/91, H120, YX10p90, LDT3-A, and 28/86, were combined to form 8 vaccination strategies, almost all of which could provide more than 70% protection effects against challenge with QX-like strain. Particularly, the best protection rate (93%) was generated by administration the polyvalent vaccine C (H120 + 28/86 + 4/91) at 1 D of age and the polyvalent vaccine B (H120 + 4/91 + YX10p90) at 10 D of age. However, all the vaccination strategies in this study cannot provide great protective effects against TW-like strain, and more vaccines should be included in studies to expand the protection spectrum of vaccine. Therefore, for the newly emerging IBV strains, immunization with polyvalent vaccines via different vaccination strategies could be used to control the prevalence of IBV in a short time, whereas developing the homologous vaccines was not always necessary.

Haemato-immunological responses and effectiveness of feed-based bivalent vaccine against Streptococcus iniae and Aeromonas hydrophila infections in hybrid red tilapia (Oreochromis mossambicus × O. niloticus).

BACKGROUND: Streptococcosis and Motile Aeromonad Septicemia (MAS) are important diseases of tilapia, Oreochromis spp. and causes huge economic losses in aquaculture globally. The feed-based vaccination may be an alternative to minimize major infectious diseases in tilapia. Thus, this study aims to evaluate the haemato-immunological responses and effectiveness of a newly developed feed-based killed bivalent vaccine against Streptococcus iniae and Aeromonas hydrophila in hybrid red tilapia. A total of 495 hybrid red tilapia of 61.23 ± 4.95 g were distributed into 5 groups (each with triplicate). The fish were immunized orally through bivalent (combined S. iniae and A. hydrophila) spray vaccine (BS group), bivalent formulate vaccine (BF group), monovalent S. iniae vaccine (MS group), monovalent A. hydrophila vaccine (MA group) and unvaccinated as a control group. The vaccine was orally administered on days 0, 14 and 42 applied feed-based bacterin at 5% body weight. The blood and spleen samples were collected from all groups on 7, 21 and 49 days post-vaccination, and also 96 h post-infection to assess their haemato-immune responses. RESULTS: Compared with the unvaccinated group, leukocyte, lymphocytes, monocytes, granulocytes counts in vaccinated groups were significantly (P < 0.05) increased on 21, 49 days post-vaccination and also 96 h post-infection, while erythrocytes, haemoglobin and haematocrit in vaccinated groups were significantly (P < 0.05) enhanced only 96 h post-infection. Additionally, the lysozyme and phagocytic activity and, serum antibody (IgM) were significantly higher (P < 0.05) against S. iniae and A. hydrophila in vaccinated groups compared to the unvaccinated group in the pre- and post-infection. Results from the challenge through co-infection with S. iniae and A. hydrophila showed the relative percent survival (RPS) in BF group was 76.67 ± 4.71%, which had the capacity to induce significant protection (P < 0.05) compared to others groups. CONCLUSIONS: This study demonstrates the bivalent formulate (BF) group could elicit significant non-specific and specific immunological responses with higher protection in hybrid red tilapia. In addition, this newly developed feed-based bivalent vaccination can be a promising technique for effective and large scale fish immunization in the aquaculture industry.

A Prospective Cohort Study on the Safety of Infant Pentavalent (DTwP-HBV-Hib) and Oral Polio Vaccines in Two South Indian Districts.

BACKGROUND: Safety of pentavalent (DTwP-HBV-Hib) vaccine has been a public concern in India and other countries. This study attempted to document the association of serious adverse events following immunization (AEFI, including hospitalizations and deaths of all causes) with the 3 doses of pentavalent and oral poliovirus (OPV) vaccines. METHODS: A cohort of 30,688 infants in 2 south Indian districts were enrolled and followed-up between October 2014 and May 2016, following their first vaccination with DTwP-HBV-Hib and OPV at public health facilities. During weekly follow-ups, by telephone or home visits, the serious AEFIs (hospitalizations and deaths) occurring any time after each vaccination until 4 weeks after third dose were documented. The incidence risk ratios (IRRs) of serious AEFIs in the first (days 0-6) and fourth weeks (days 21-27) after the vaccine doses were compared using the poisson regression analysis. RESULTS: Of the 30,688 infants enrolled, 30,208 received their third doses of vaccines. During the 4-week periods following each vaccination, there were 365 hospitalizations and 17 deaths. Adjusted incidence risk ratio of 3 doses combined for post-vaccination serious AEFIs during the first week compared with fourth week was 0.8 [95% confidence interval: 0.6-1.0]. CONCLUSIONS: There was no increased risk of a serious AEFIs during the first week after any of the 3 doses of pentavalent and OPV vaccination compared with the fourth week. In the absence of any temporal clustering, mortality and hospitalization rates observed in vaccinated infants probably reflects the natural occurrence of such events.

Safety of measles-containing vaccines in post-marketing surveillance in Anhui, China.

The safety of measles vaccination is of great interest and importance to public health practice and the general society. We have analyzed the adverse events following immunization (AEFIs) of currently used measles-containing vaccines (including live attenuated measles vaccine, live attenuated measles and rubella combined vaccine, live attenuated measles and mumps combined vaccine, live attenuated Measles, Mumps and Rubella Combined Vaccine) in Anhui Province, China. From 2009 to 2014, 9.9 million doses of measles-containing vaccines were administrated and 1893 AEFIs were found (191.4 per million doses), of which, 33 serious AEFIs (3.3 per million vaccine doses) were reported. 59.4% (1124 cases) were male cases, and 85.1% (1611 cases) occurred in persons aged < 1 year. 93.3% (1766 cases) occurred at the first dose of vaccination and 95.9% (1815 cases) were found within 3 days after vaccination. This study presents up-to-date data and suggests that the measles-containing vaccines used in Anhui Province of China are safe.

Safety, immune lot-to-lot consistency and non-inferiority of a fully liquid pentavalent DTwp-HepB-Hib vaccine in healthy Indian toddlers and infants.

Pentavalent combination vaccines are important tools to strengthen the immunization programs in numerous countries throughout the world. A large number of countries have recognized the value of combination vaccines and have introduced whole cell pentavalent vaccines into their immunization programs. A phase III, multi-center, randomized, single blinded study of a fully liquid pentavalent DTwP-HepB-Hib investigational vaccine (Shan5™) was conducted across India in 2 cohorts: 15 toddlers were evaluated for safety and immunogenicity following a single booster dose (Cohort 1) followed by 1085 infants (Cohort 2) evaluated for immunogenicity and safety following 3-dose primary immunization of the investigational vaccine or a locally licensed comparator vaccine (Pentavac SD). Immune consistency analysis among 3 lots of the investigational vaccine, and immune non-inferiority analysis of pooled (3 lots) data of investigational vaccine vs. comparator vaccine were carried out in cohort 2. The vaccines demonstrated comparable safety and immune responses in cohort 1. In cohort 2, equivalent immune consistency among 3 lots was observed for all antigens except whole cell pertussis antigens, where a marginal variation was observed which was linked to the low power of the test and concluded to not have any clinical significance. Immune non-inferiority against the comparator vaccine was demonstrated for all 5 antigens. Safety results were comparable between vaccine groups. This investigational, fully-liquid, whole-cell pertussis (wP) containing new pentavalent vaccine was found to be safe and immunologically non-inferior to the licensed comparator vaccine.

Effects of simultaneous immunization of Haemophilus influenzae type b conjugate vaccine and diphtheria-tetanus-acellular pertussis vaccine on anti-tetanus potencies in mice, guinea pigs, and rats.

Haemophilus influenzae type b vaccine conjugated with tetanus toxoid (HibT) was licensed for use in childhood immunization in Japan in 2007. As adsorbed diphtheria-tetanus-acellular pertussis (DTaP) combined with HibT vaccine has not been introduced in Japan, DTaP and HibT vaccines are injected at separate sites with a similar immunization schedule. There are various interfering or stimulatory effects between components of combined vaccines contained in DTaP and HibT vaccines. In this study, we investigated the effect of HibT containing combination vaccines on anti-tetanus potencies by using animal models (mouse, guinea pig, and rat). HibT vaccine and HibT components of imported DTaP-HibT vaccine alone showed comparable or higher anti-tetanus potency than DTaP vaccine and DTaP-containing components of combination vaccines. Mixing these components before injection resulted in potencies greater than the sum of individual potencies. Injecting individual components at separate sites in animals resulted in potency roughly equivalent to the sum of the individual potencies. These results provide useful information regarding the use of HibT-containing multivalent vaccines in childhood immunization.

Vaccines for typhoid fever and other salmonelloses.

PURPOSE OF REVIEW: This review summarizes the recent advances in vaccination against Salmonella enterica serovar Typhi and highlights the data supporting the development of next generation vaccines to address paratyphoid fever and invasive nontyphoidal Salmonella (iNTS) disease. RECENT FINDINGS: There has been increasing awareness of the disease burden caused by S. Typhi particularly in Africa and greater recognition of S. Paratyphi A's contribution to enteric fever episodes throughout Asia. Groups have been working to improve the existing typhoid vaccines and provide comprehensive data on the feasibility of their implementation in endemic settings. These data have resulted in modifications to the recommendations for typhoid vaccination in traveller markets and endemic settings, and has also led to the development of S. Paratyphi A vaccine components that can be combined with existing typhoid vaccines to generate bivalent formulations against enteric fever. The epidemiology of iNTS serovars as cause of appreciable morbidity and mortality in Africa, and the need for vaccines, has also become more widely appreciated. SUMMARY: Current typhoid vaccines, although moderately effective for short periods of time, cannot be used in all age groups and only target one of the clinically relevant Salmonella serovars. Greater effort must be placed on the development and implementation of improved vaccines for the disease burden resulting from Typhi, Paratyphi A or iNTS infections.

Combined vaccines - case study.

Application of the principles outlined in the WHO Guideline on Stability Evaluation of Vaccines is complicated by the nature of combination vaccines. Differences in degradation rates among the immunogens impose the restriction that shelf life is based on the most labile component. There is also a testing challenge with numerous components held at different stages of production.

Antibody induced by immunization with the Jeryl Lynn mumps vaccine strain effectively neutralizes a heterologous wild-type mumps virus associated with a large outbreak.

Recent mumps outbreaks in older vaccinated populations were caused primarily by genotype G viruses, which are phylogenetically distinct from the genotype A vaccine strains used in the countries affected by the outbreaks. This finding suggests that genotype A vaccine strains could have reduced efficacy against heterologous mumps viruses. The remote history of vaccination also suggests that waning immunity could have contributed to susceptibility. To examine these issues, we obtained consecutive serum samples from children at different intervals after vaccination and assayed the ability of these samples to neutralize the genotype A Jeryl Lynn mumps virus vaccine strain and a genotype G wild-type virus obtained during the mumps outbreak that occurred in the United States in 2006. Although the geometric mean neutralizing antibody titers against the genotype G virus were approximately one-half the titers measured against the vaccine strain, and although titers to both viruses decreased with time after vaccination, antibody induced by immunization with the Jeryl Lynn mumps vaccine strain effectively neutralized the outbreak-associated virus at all time points tested.

WHO Working Group on revision of the Manual of Laboratory Methods for Testing DTP Vaccines-Report of two meetings held on 20-21 July 2006 and 28-30 March 2007, Geneva, Switzerland.

This report reflects the discussion and conclusions of a WHO group of experts from National Regulatory Authorities (NRAs), National Control Laboratories (NCLs), vaccine industries and other relevant institutions involved in standardization and control of diphtheria, tetanus and pertussis vaccines (DTP), held on 20-21 July 2006 and 28-30 March 2007, in Geneva Switzerland for the revision of WHO Manual for quality control of DTP vaccines. Taking into account recent developments and standardization in quality control methods and the revision of WHO recommendations for D, T, P vaccines, and a need for updating the manual has been recognized. In these two meetings the current situation of quality control methods in terms of potency, safety and identity tests for DTP vaccines and statistical analysis of data were reviewed. Based on the WHO recommendations and recent validation of testing methods, the content of current manual were reviewed and discussed. The group agreed that the principles to be observed in selecting methods included identifying those critical for assuring safety, efficacy and quality and which were consistent with WHO recommendations/requirements. Methods that were well recognized but not yet included in current Recommendations should be taken into account. These would include in vivo and/or in vitro methods for determining potency, safety testing and identity. The statistical analysis of the data should be revised and updated. It was noted that the mouse based assays for toxoid potency were still quite widely used and it was desirable to establish appropriate standards for these to enable the results to be related to the standard guinea pig assays. The working group was met again to review the first drafts and to input further suggestions or amendments to the contributions of the drafting groups. The revised manual was to be finalized and published by WHO.

Comparison of the safety and immunogenicity of a refrigerator-stable versus a frozen formulation of ProQuad (measles, mumps, rubella, and varicella virus vaccine live).

OBJECTIVE: A refrigerator-stable formulation of ProQuad has been developed to expand the utility of ProQuad to areas in which maintenance of a frozen cold chain (-15 degrees C or colder) during storage and transport may not be feasible. The objective of this study was to demonstrate that the immunogenicity and safety profiles of a refrigerator-stable formulation of ProQuad are similar to the recently licensed frozen formulation. METHODS: In this double-blind, randomized, multicenter study, healthy 12- to 23-month-old children with negative vaccination and clinical histories for measles, mumps, rubella, varicella, and zoster were vaccinated with either the refrigerator-stable formulation of ProQuad (N = 1006) or the frozen formulation of ProQuad (N = 513). Patients were followed for 42 days after vaccination for adverse experiences. Immunogenicity was evaluated 6 weeks after vaccination. RESULTS: The refrigerator-stable formulation of ProQuad was generally well tolerated. The incidence of adverse experiences was similar between groups. No vaccine-related serious adverse experiences were reported. For both groups, the response rate was > or = 97.7% for measles, mumps, and rubella, and the percentage of patients with a varicella zoster virus antibody titer of > or = 5 U/mL glycoprotein antigen-based enzyme-linked immunosorbent assay after vaccination was > or = 88.8%. The geometric mean titers for all antigens were numerically slightly higher in patients who received the refrigerator-stable formulation. CONCLUSIONS: The refrigerator-stable formulation of ProQuad is generally well tolerated, highly immunogenic, and noninferior in terms of postvaccination antibody responses. This refrigerator-stable formulation may improve ease of vaccine administration, increase use of the vaccine throughout the world because of its improved storage conditions, and replace the frozen formulation of ProQuad or any dose of M-M-RII and Varivax in routine practice.

The safety and immunogenicity of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children: a study of manufacturing consistency and persistence of antibody.

BACKGROUND: This clinical trial was conducted to demonstrate that each of 3 consistency lots of a combined measles, mumps, rubella and varicella vaccine (MMRV) would be well tolerated, induce clinically acceptable and similar immune responses to each antigen and induce immune responses similar to measles, mumps and rubella vaccine (MMR) administered concomitantly with varicella vaccine (V). An additional objective was to evaluate the persistence of antibodies 1 year postvaccination. METHODS: Study participants 12 to 23 months of age received a single injection of either one of 3 consistency lots of MMRV or MMR + V administered at separate injection sites. RESULTS: A total of 3,928 healthy children were enrolled at study sites in the United States and Canada. Immune responses to measles, mumps, rubella and varicella in children immunized with each of 3 lots of MMRV were similar and the combined response to all 3 lots was comparable to that of the control group. The 1-year antibody persistence rates for measles, mumps, rubella and varicella viruses were each greater than 95% and comparable among the recipients of the 3 consistency lots of MMRV and the control group. All vaccines were generally well tolerated during the 42 days after vaccination and the overall incidence of adverse experiences was comparable between recipients of MMRV and MMR + V. Rates of fever (temperature >or=38.9 degrees C oral equivalent or tactile) were greater in recipients of MMRV than in recipients of MMR + V (39.1% versus 33.1%, P = 0.001). Fevers were transient and there was no difference in the incidence of febrile seizures. CONCLUSIONS: MMRV was generally well tolerated and had comparable immunogenicity and overall safety profiles to MMR + V administered concomitantly. Long-term persistence of antibodies after receipt of MMRV is expected based on similar antibody titers against all 4 antigens 1 year postvaccination compared with recipients of MMR and V.

Regulation and standardization of IPV and IPV combination vaccines.

Inactivated poliovirus vaccine (IPV) is not only increasingly used on a global basis but also is a component of many combination vaccines. Standardization and control of IPV continues to be a challenge for manufacturers and regulators. A rat immunogenicity assay is currently recommended by many authorities, including WHO, as the definitive in vivo potency. Alternative in vitro assays to determine D-antigen content have been developed and are routinely used in some countries to assess IPV potency assay. However, the other less reliable in vivo immunogenicity assays are also used (e.g. monkey, chick). We review some of the regulatory challenges facing current and future IPV assessment, with a focus on the relevance of in vivo and in vitro tests, considerations for Sabin derived IPV and discussion of future efforts for standardization.

Collaborative study for the validation of serological methods for potency testing of diphtheria toxoid vaccine (part 2).

The study is a contribution to the EDQM's efforts to meet some of the expectations of the 3 Rs: Replacement, Reduction and Refinement of animal assays as proposed by Russell and Burch in 1959 and adopted by the European Union in 1986, and specifically to validate alternative assays to replace, for batch-release purposes, the European Pharmacopoeia (Ph. Eur.) in vivo direct challenge procedures for the potency determination of diphtheria toxoid vaccines. The study results may be used in support of the replacement of the multi-dilution direct challenge procedures in different animal models by a single dilution serology test, where appropriate, and to use sera from the same animals for potency testing of several components in combined vaccines. With regard to the latter, the present study explores the possibility of testing both diphtheria and tetanus toxoid potencies using serum from the same animals.

Comparative efficacy of Rubini, Jeryl-Lynn and Urabe mumps vaccine in an Asian population.

OBJECTIVE: The comparative efficacy of the three mumps vaccine strains (Jeryl-Lynn, Urabe and Rubini) was conducted in an Asian population from data arising from an epidemiological investigation of seven institutional outbreaks of mumps in Singapore. METHODS: Demographic information (gender, age, ethnic group), clinical presentation and vaccination history (date and place of mumps vaccination, type of mumps vaccine received) of all children who attended the six childcare centres and one primary school where outbreaks of 20 or more cases of mumps occurred in 1999 were collected. The attack rate of the unvaccinated group and the attack rates of the vaccine groups (for each vaccine strain) were determined and the vaccine efficacy of the three vaccines calculated. RESULTS: The vaccine efficacy of the Jeryl-Lynn strain, Urabe strain and Rubini strain mumps vaccine were 80.7, 54.4 and -55.3%, respectively. CONCLUSION: Rubini strain mumps vaccine conferred no protection and has since been deregistered in Singapore.

Diphtheria-tetanus-pertussis (DTP) combination vaccines and evaluation of pertussis immune responses.

Diphtheria-tetanus-pertussis (DTP) combination vaccines based on inactivated whole-cell Bordetella pertussis (DTPw) or purified acellular pertussis components (DTPa) facilitate vaccine administration and will allow further co-administration such as with pneumococcal conjugates. Safety and immunogenicity studies are needed to demonstrate non-inferiority between combinations and the separate vaccines. The immunological non-inferiority is based on threshold antibody levels that represent correlates of protection. However, in case of pertussis, correlates of protection have not been defined or accepted. We describe the clinical evaluation of DTPa- and DTPw-based combinations and demonstrate their immunological non-inferiority as compared to their separately administered licensed counterparts. With respect to antibody responses against pertussis, a number of evaluations (vaccine response rates and geometric mean concentrations (GMCs) for anti-PT, anti-FHA, anti-PRN or anti-BPT; reverse cumulative distribution curves) are described. We also demonstrate that the B. pertussis mouse lung clearance model is able to predict clinical efficacy of licensed DTPa and DTPw vaccines and represents a useful tool to evaluate new combination vaccines.