Development Of Combination Vaccines Research Articles

Immunogenicity and Efficacy of Combined mRNA Vaccine Against Influenza and SARS-CoV-2 in Mice Animal Models.

Background. The combined or multivalent vaccines are actively used in pediatric practice and offer a series of advantages, including a reduced number of injections and visits to the doctor, simplicity of the vaccination schedule and minimization of side effects, easier vaccine monitoring and storage, and lower vaccination costs. The practice of widespread use of the combined vaccines has shown the potential to increase vaccination coverage against single infections. The mRNA platform has been shown to be effective against the COVID-19 pandemic and enables the development of combined vaccines. There are currently no mRNA-based combined vaccines approved for use in humans. Some studies have shown that different mRNA components in a vaccine can interact to increase or decrease the immunogenicity and efficacy of the combined vaccine. Objectives. In the present study, we investigated the possibility of combining the mRNA vaccines, encoding seasonal influenza and SARS-CoV-2 antigens. In our previous works, both vaccine candidates have shown excellent immunogenicity and efficacy profiles in mice. Methods. The mRNA-LNPs were prepared by microfluidic mixing, immunogenicity in mice was assessed by hemagglutination inhibition assay, enzyme-linked immunoassay and virus neutralization assay. Immunological efficacy was assessed in a mouse viral challenge model. Results. In this work, we demonstrated that the individual mRNA components of the combined vaccine did not affect the immunogenicity level of each other. The combined vaccine demonstrated excellent protective efficacy, providing a 100% survival rate when mice were infected with the H1N1 influenza virus and reducing the viral load in the lungs. Four days after the challenge with SARS-CoV-2 EG.5.1.1., no viable virus and low levels of detectable viral RNA were observed in the lungs of vaccinated mice. Conclusions. The combination does not lead to mutual interference between the individual vaccines. We believe that such a combined mRNA-based vaccine could be a good alternative to separated human vaccinations for the prevention of COVID-19 and influenza.

Analysis of the Impact of Inactivated A71 Vaccine on the Incidence of Hand-Foot-Mouth Disease in Pudong New Area, Shanghai.

The aim of this study was to investigate the level of inactivated A71 (EV-A71) vaccination in Pudong New Area of Shanghai and its effects on the epidemiology and pathogen spectrum of hand-foot-mouth disease (HFMD) in this area, as well as to provide a basis for improving the prevention and control strategy of HFMD in this area. Data were collected from the "Comprehensive Management Cloud Platform for Immunization Program" system from December 2016 to December 2022. The data on HFMD cases from January 2012 to December 2022 were extracted from the "China Information System for Disease Control and Prevention". A total of 484,056 doses were administered. The vaccination rate of the first dose was 14.03%, and the full vaccination rate was 13.33%. There were significant differences between the first dose and the full vaccination rate in different years (χ2 = 46,538.831, p < 0.001, χ2 = 50,013.946, p < 0.001). A total of 91625 cases of HFMD were reported, including 58 severe cases, and no deaths. Before and after the administration of the inactivated EV-A71 vaccine, there were statistical differences in the distribution of HFMD cases in terms of gender, household registration, occupation, and age (p < 0.001). The etiological surveillance results showed that the rate of enterovirus positivity was 84.15%, with 9.85% being EV-A71, 23.74% CV-A16, and 50.56% non-EV-A71 and non-CV-A16. The coverage rate of the inactivated EV-A71 vaccine in Pudong New Area was not high, and the incidence of HFMD showed a downward trend after the postmarketing of the vaccine. The majority of HFMD infections were non-EV-A71 and non-CV-A16, with CV-A6 accounting for the highest proportion. It is recommended to accelerate the development of combined vaccines to provide more antibody protection.

Virus-like particle-based multipathogen vaccine of FMD and SVA elicits balanced and broad protective efficacy in mice and pigs

Inactivated vaccines lack the capability to serologically differentiate between infected and vaccinated animals, thereby impeding the effective eradication of pathogen. Conversely, vaccines based on virus-like particles (VLPs) emulate natural viruses in both size and antigenic structure, presenting a promising alternative to overcome these limitations. As the complexity of swine infectious diseases increases, the increase of vaccine types and doses may intensify the stress response. This exacerbation can lead to diminished productivity, failure of immunization, and elevated costs. Given the critical dynamics of co-infection and the clinically indistinguishable symptoms associated with foot-and-mouth disease virus (FMDV) and senecavirus A (SVA), there is a dire need for an efficacious intervention. To address these challenges, we developed a combined vaccine composed of three distinct VLPs, specifically designed to target SVA and FMDV serotypes O and A. Our research demonstrates that this trivalent VLP vaccine induces antigen-specific and robust serum antibody responses, comparable to those produced by the respective monovalent vaccines. Moreover, the immune sera from the combined VLP vaccine strongly neutralized FMDV type A and O, and SVA, with neutralization titers comparable to those of the individual vaccines, indicating a high level of immunogenic compatibility among the three VLP components. Importantly, the combined VLPs vaccines-immunized sera conferred efficient protection against single or mixed infections with FMDV type A and O, and SVA viruses in pigs. In contrast, individual vaccines could only protect pigs against homologous virus infections and not against heterologous challenges. This study presents a novel combined vaccines candidate against FMD and SVA, and provides new insights for the development of combination vaccines for other viral swine diseases.

A subunit-based influenza/SARS-CoV-2 Omicron combined vaccine induced potent protective immunity in BALB/c mice.

Infection with influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a significant risk to human life, health, and the global economy. Vaccination is one of the most effective strategies in the fight against infectious viruses. In this study, we, for the first time, have evaluated the immunogenicity and protective effect of an influenza/SARS-CoV-2 Omicron subunit combined vaccine adjuvanted with MF59 and administered to BALB/c mice. Results showed that the combined vaccine induced high levels of IgG, IgG1 , and IgG2a antibodies, as well as influenza A H1N1/California/2009 virus-specific hemagglutination-inhibiting antibodies in BALB/c mice. Moreover, this subunit combined vaccine induced high titers of neutralization antibodies against SARS-CoV-2 Omicron sublineage BA.5 pseudovirus and effectively reduced the viral load of authentic SARS-CoV-2 Omicron sublineage BA.5.2 in the cell culture supernatants. These results suggested that this subunit combined vaccine achieved protective effect against both H1N1 A/California/07/2009 strain and SARS-CoV-2 Omicron BA.5.2 variant. It is therefore expected that this study will establish the scientific foundation for the next-step development of combined vaccines against other strains or variants of IAV and SARS-CoV-2.

Interactions among acute respiratory viruses in Beijing, Chongqing, Guangzhou, and Shanghai, China, 2009-2019.

A viral infection can modify the risk to subsequent viral infections via cross-protective immunity, increased immunopathology, or disease-driven behavioral change. There is limited understanding of virus-virus interactions due to lack of long-term population-level data. Our study leverages passive surveillance data of 10 human acute respiratory viruses from Beijing, Chongqing, Guangzhou, and Shanghai collected during 2009 to 2019: influenza A and B viruses; respiratory syncytial virus A and B; human parainfluenza virus (HPIV), adenovirus, metapneumovirus (HMPV), coronavirus, bocavirus (HBoV), and rhinovirus (HRV). We used a multivariate Bayesian hierarchical model to evaluate correlations in monthly prevalence of test-positive samples between virus pairs, adjusting for potential confounders. Of 101,643 lab-tested patients, 33,650 tested positive for any acute respiratory virus, and 4,113 were co-infected with multiple viruses. After adjusting for intrinsic seasonality, long-term trends and multiple comparisons, Bayesian multivariate modeling found positive correlations for HPIV/HRV in all cities and for HBoV/HRV and HBoV/HMPV in three cities. Models restricted to children further revealed statistically significant associations for another ten pairs in three of the four cities. In contrast, no consistent correlation across cities was found among adults. Most virus-virus interactions exhibited substantial spatial heterogeneity. There was strong evidence for interactions among common respiratory viruses in highly populated urban settings. Consistent positive interactions across multiple cities were observed in viruses known to typically infect children. Future intervention programs such as development of combination vaccines may consider spatially consistent virus-virus interactions for more effective control.

Recent Advances in mRNA Vaccine Development

Messenger RNA vaccines are vaccine that utilizes a small segment of genetic material, messenger RNA (mRNA), to provide instructions to cells to produce a specific protein. This mRNA is synthesized in a laboratory and packaged into lipid nanoparticles, which protect and facilitate its entry into cells for protein synthesis. Upon injection into the muscle of the recipient, the mRNA instructs cells to produce a protein that is displayed on the surface of the cell, triggering an immune response. The immune system then produces antibodies and activates immune cells to target and eliminate the protein, while also generating memory cells to respond quickly in the event of future pathogen encounters. Available mRNA vaccines, such as Pfizer-BioNTech and Moderna, were developed and authorized for emergency use within a year. These vaccines require extensive cold chain storage, antigen delivery, potential immune response variability optimization, and sophisticated manufacturing process. To improve their effectiveness, stability, and delivery, efforts are underway to explore next-generation mRNA vaccines. Research is focused on enhancing the stability of mRNA vaccines, particularly their temperature sensitivity, to facilitate easier storage and distribution. Self-amplifying mRNA vaccines are also being developed to generate multiple copies of mRNA within cells, potentially leading to a higher production of protein and a stronger immune response. Studies are also exploring new delivery systems using specialized nanoparticles and liposomes to specifically target certain immune cells. Additionally, the development of combination vaccines, including multiple mRNA sequences in single vaccine, is being investigated to protect against multiple strains or variants of particular pathogen simultaneously. Direct delivery of mRNA vaccines into the skin is being explored as a means of enhancing immune response and reducing the required vaccine dose. In summary, messenger RNA vaccines represent a promising new approach to vaccination, with ongoing research aimed at improving their effectiveness, stability, and delivery

Efficacy of bivalent vaccine against Aeromonas salmonicida and Edwardsiella tarda infections in turbot.

In recent years, more than one pathogenic organism has usually been isolated from diseased turbot Scophthalmus maximus, creating a pressing need for the development of combination vaccines to prevent fish diseases brought on simultaneously by various infections. In this study, the inactivated bivalent vaccine of Aeromonas salmonicida and Edwardsiella tarda was prepared by the formalin inactivation method. After challenge with A. salmonicida and E. tarda at 4 weeks post-vaccination in turbot, the relative percentage survival (RPS) of the inactivated bivalent vaccine was 77.1%. In addition, we assessed the effects of the inactivated bivalent vaccine and evaluated the immunological processes after immunization in a turbot model. Serum antibody titer and lysozyme activity of the vaccinated group were both upregulated and higher than that in control group after vaccination. The expression levels of genes (TLR2, IL-1β, CD4, MHCI, MHCⅡ) that related to antigen recognition, processing and presentation were also studied in the liver, spleen and kidney tissues of vaccinated turbot. All the detected genes in the vaccinated group had a significant upward trend, and most of them reached the maximum value at 3-4 weeks, which had significant differences from the control group, suggesting that antigen recognition, processing and presentation pathway was activated by the inactivated bivalent vaccine. Our study provides a basis for further application of the killed bivalent vaccine against A. salmonicida and E. tarda in turbot, making it good potential that can be applied in aquaculture.

Co-administration of COVID-19 and influenza vaccines

It will also be critical to continue assessing co-administration of other vaccines in the future, since COVID-19 vaccine boosters are likely to be part of routine immunization in the future, at least in selected vulnerable population. It will be particularly critical to assess the safety of simultaneous immunization with vaccines that are equally reactogenic than the current COVID-19 vaccines, such as adjuvanted vaccines. Eventually, the development of combination vaccines in adults, following the model of pediatric vaccines, is also urgently needed to optimize vaccine coverage and alleviate any remaining concerns on vaccine co-administration.

Display of Streptococcus iniae α-Enolase on the Surface of Virus-Like Particles (VLPs) of Nervous Necrosis Virus (NNV) Using SpyTag/SpyCatcher.

Virus-like particle (VLP)-based vaccines are promising candidates for overcoming the safety problems of live vaccines and weak immunogenicity of subunit vaccines. VLPs can be used as a platform for the development of combined vaccines by expressing foreign antigens, and foreign antigens can be displayed on the surface of VLPs by conjugation. In the present study, to use nervous necrosis virus (NNV) VLPs as a delivery tool for Streptococcus iniae α-enolase by displaying on the VLP's surface, the split-intein (SpyTag/SpyCatcher) conjugation system was used. NNV capsid protein fused to SpyTag (Capsid-SpyTag) and S. iniae α-enolase fused to SpyCatcher (α-enolase-SpyCatcher) were recombinantly produced, then mixed in various ratios. A ratio of Capsid-SpyTag to α-enolase-SpyCatcher of 1 to 1.5 showed the highest coupling efficiency corresponding to 83-92% of coupled capsid protein dimer and 32-52% of coupled capsid protein monomer. In TEM observation, VLP of Capsid-SpyTag had a regular shape and size of about 40 nm, while VLP fused with α-enolase-SpyCatcher showed an irregular shape and size of about 40-50 nm in diameter. In preliminary immunization experiments, olive flounder (Paralichthys olivaceus) and zebrafish (Danio rerio) immunized with VLP fused with α-enolase-SpyCatcher showed the lowest cumulative mortality against S. iniae infection.

How did the adoption of wP-pentavalent affect the global paediatric vaccine coverage rate? A multicountry panel data analysis

ObjectivesSeveral studies have highlighted the effects of combination vaccines on immunisation coverage at the national or subnational level. This study examined the effects globally. Worldwide introduction of whole-cell pertussis pentavalent...

Separation of three strains of polio virus by capillary zone electrophoresis and study of their interaction with aluminum oxyhydroxide

The development of combination vaccines is essential to reduce the number of injections, shorten vaccination schedules and increase vaccination coverage. Vaccine adjuvants are used to modulate and enhance the immune response induced by the antigens. To support the development of combination vaccines, the study of antigen-adjuvant interactions in the final vaccine formulations is required as interaction competitions may take place between the different antigens. In the present work, a capillary zone electrophoresis (CZE) methodology was firstly optimized on six model proteins, namely bovine serum albumin, β-lactoglobulin, myoglobin, ribonuclease A, cytochrome C and lysozyme. A cationic dynamic coating (polybrene) and a zwitterionic amino acid additive (β-alanine) in the background electrolyte were used to reduce the phenomena of protein adsorption on the inner wall of the capillary and thus optimize the separation efficiency of the proteins. The developed methodology was then used to separate three strains from inactivated polio virus, each strain being a whole virus composed of copies of 4 viral proteins and study their interaction with aluminum oxyhydroxide. The antigen-adjuvant interactions could be modulated by addition of phosphate ions playing the role of competitors for the poliovirus.

Detection of peste des petits ruminants and concurrent secondary diseases in sheep and goats in Ngorongoro district, Tanzania

Small ruminants play an important role in the livelihoods of resource-constrained communities. This study was initiated because of a massive outbreak of a respiratory disease in sheep and goats in Loliondo area in Ngorongoro district of Arusha region in Tanzania in 2016. During flock examination, a total of 240 serum samples and 61 nasal swabs were collected. Antibodies to small ruminant morbillivirus, causative agent of peste des petits ruminants (PPR), were detected from sera using a competitive enzyme-linked immunosorbent assay. A multiplex reverse transcription real-time polymerase chain reaction assay was used to detect four pathogens: small ruminant morbillivirus, Mycoplasma capricolum subspecies capripneumoniae, Pasteurella multocida, and Capripoxvirus from the nasal swabs. Overall seroprevalence of PPR was 74.6%, with all four pathogens detected from nasal swabs. Co-infections of small ruminant morbillivirus and Mycoplasma capricolum subspecies capripneumoniae, small ruminant morbillivirus and Capripoxvirus, small ruminant morbillivirus and Pasteurella multocida, and Mycoplasma capricolum subspecies capripneumoniae and Capripoxvirus were also detected. Presence of PPR and the other diseases in this study provided insight into the severity of the outbreak in sheep and goats in Ngorongoro district. Thus, laboratory confirmation is critical for prompt and appropriate interventions to be made for control of diseases in sheep and goats with similar clinical signs. The findings also call for research into development of combined vaccines targeting common diseases of small ruminants in Tanzania.

EXPERIENCE OF USE OF DTAP HEXAVACCINE AT THE VACCINAL PREVENTION UNIT FOR CHILDREN WITH HEALTH DEVIATIONS OF THE SCIENTIFIC CENTER OF CHILDREN’S HEALTH (FEDERAL STATE BUDGETARY SCIENTIFIC INSTITUTION)

научный биометрический журнал, который знакомит читателя с клиническими рекомендациями и особенностями применения лекарственных и вакцинных средств у детей, предоставляет исчерпывающую информацию о воздействии лекарственных средств на плод, о проводимых в

Development of combined vaccines for rabies and immunocontraception

Rabies prevention and appropriate population management of free-ranging animals have an important role to play in the eventual elimination of rabies in dogs. An effective sterilant based on rabies vaccines has the potential to create a supportive measure of public acceptability and to reduce associated clinic visit costs. We inserted the coding sequence of gonadotropin-releasing hormone (GnRH) into different locations within the rabies virus ERA glycoprotein (G) gene, and demonstrated that the amino terminus (N), antigenic site IIa, and the junction between the ecto- and cytoplasmic domains (C) of the G were suitable sites for GnRH insertion. The rescued recombinant rabies viruses ERA-N-GnRH and ERA-C-GnRH grew as well as the parental ERA virus, reaching 1×109ffu/ml in cell culture. Insertion and expression of the GnRH were stable in the viruses after multiple passages in vitro. To increase immunogenicity of the GnRH peptide, two copies of GnRH, aligned in tandem, were fused to the N terminus of the G. The recombinant rabies virus ERA-N-2GnRH was recovered and grown to high titers in cell culture. All GnRH-carrying rabies viruses induced antibodies against GnRH in immunized mice and protected 100% of the animals after rabies virus challenge. The recombinant viruses reacted strongly with the serum from a GonaCon™-immunized animal. The GnRH-carrying rabies viruses have significant potential in rabies and animal population control.

Review of 8 years of experience with Infanrix hexa™ (DTPa–HBV–IPV/Hib hexavalent vaccine)

Combination vaccines that include multiple antigens within one formulation are now widely accepted as an effective means of eliciting protection against several diseases at the same time. Owing to improvements in quality and convenient modes of administration, they have become part of routine pediatric practice. Hexavalent vaccines, including diphtheria, tetanus, pertussis, hepatitis B, polio and Haemophilus influenzae type b antigens represent the latest advance in the development of combination vaccines. Over 8 years since its first licensure, this review looks at the immunogenicity, efficacy and safety profile of the only hexavalent pediatric vaccine currently in use – Infanrix hexa™ (diphtheria, tetanus, acellular pertusis–hepatitis B virus–inactivated poliovirus vaccine/Haemophilus influenzae type b vaccine [DTPa–HBV–IPV/Hib]; GlaxoSmithKline Biologicals, Rixensart, Belgium) – through published clinical trials and postmarketing surveillance data. These data show DTPa–HBV–IPV/Hib to be highly immunogenic and well tolerated across a range of different primary and booster vaccination schedules, as well as when administered concomitantly with other licensed vaccines (e.g., pneumococcal conjugate vaccine). Additional issues surrounding the use of hexavalent vaccines are also reviewed.

Studies of equivalence in clinical vaccine research

The development of combination vaccines as well as the improved manufacture of vaccines have resulted in the need for clinical studies seeking equivalence or non-inferiority as investigators seek to demonstrate that combination vaccines achieve the same levels of efficacy, immunogenicity, and safety as their individual counterparts. Given the nature of the statistical analysis, studies of equivalence require particular attention to sample size. The current double-significance method of Neyman–Pearson attempts to address problems with equivalence testing, but it leads to very large sample sizes and illogical results. With such large samples, one can find a clinically trivial difference that is still statistically significant. The late Professor Alvan R. Feinstein proposed a more logical approach that would call for smaller, more workable sample sizes. Understanding the issues involved in sample size calculations for such studies is important to those who design clinical vaccine studies. The implications of the calculations will have far-reaching effects on the feasibility of the study such as availability of subjects, the success with recruitment, and the overall expenses. In fact, the feasibility issues may prevent the study being undertaken at all.

The place of accelerated schedules for hepatitis A and B vaccinations.

The availability of accelerated schedules of vaccination, as well as the development of combination vaccines, has enhanced the methods of protection against infectious disease, in particular that of hepatitis A and B viruses. The benefits of using accelerated schedules include: (i) enhanced adherence to and subsequent completion of vaccine courses; (ii) convenience for the recipient of the vaccine; (iii) reduced administration costs of providing the vaccine; and, most importantly, (iv) the ability to provide protection against these serious infections to those who will be imminently exposed to the risk and so require protection as quickly as possible. Active immunisation against both hepatitis A and B viruses has only been recognised within the last 20 years. During this time clinical studies have demonstrated the safety and efficacy of administering the monovalent hepatitis B vaccine by way of accelerated schedules. There are now several accelerated schedules of administration of hepatitis B vaccine which can be tailored to the needs of the individual at risk of exposure to infection. One such schedule allows the primary course to be administered within a period of 1 month. This schedule of day 0, 7 and 21, with a booster at 12 months, is licensed for use with the recombinant hepatitis B vaccine Engerix B and results in a seroprotection rate of 65% at day 28 which increases to 99% at month 13. In more recent years, the development of a multivalent or combination vaccine against hepatitis A and B (Twinrix) has been a welcome advance in the protection against viral hepatitis, and has been of particular benefit to those who are at risk of infection with both viruses. The advantages of accelerated schedules have also been recognised with this combination vaccine. The primary course may be administered within a period of 1 month so providing protection for those at risk and, in particular, the last minute traveller.

Vaccinology: past achievements, present roadblocks and future promises

Of all the branches of modern medicine, vaccinology can claim to be the one that has contributed most to the relief of human misery and the spectacular increase in life expectancy in the last two centuries. It is the only science that has eradicated an infectious disease—smallpox—responsible for 8–20% of all deaths in several European countries in the 18th century. Other disabling and lethal diseases, like poliomyelitis and measles, are targeted for eradication. Currently, it is estimated that immunization saves the lives of 3 million children a year but 2 million more lives could be saved by existing vaccines. The success of vaccines in controlling and eliminating diseases has, paradoxically, been the cause of a revival of the anti-vaccination movement which in the absence, in developed countries, of many erstwhile common infectious diseases such as diphtheria, tetanus, polio, pertussis, measles, rubella and mumps has come to believe that vaccination is not only no longer necessary but is even dangerous. This is because it accepts, as “reactions”, any untoward health event that occurs after administration of a vaccine. Most vaccine “reactions”, therefore, appear to be more frequent than vaccine-preventable diseases. Public Health Authorities, aware of the great value of vaccines to society, are facing an uphill battle to get them accepted by a growing proportion of so-called educated minorities, thus endangering disease elimination. Other developments, in the last two decades, that have hampered vaccine usage have been the exploding costs of research, development and manufacture of new vaccines and the emphasis still placed on therapy in preference to prevention in medicine. This has led to the erroneous perception that vaccines are expensive although they are, in most cases, more cost-effective than the popular wait-see-treat approach. A favorable trend for vaccinology has been fuelled by recent major breakthroughs in the sciences of immunology, molecular biology, genomics, proteomics, physico-chemistry and computers that promise a bright future for prevention, not only of acute infectious diseases, but also treatment of conditions like chronic infections, allergy, auto-immune diseases and cancer where some malfunctioning of the immune system is thought to play a part. Vaccines are being made more user-friendly by the development of combined vaccines and less painful and invasive inoculation techniques than the traditional syringe and needle. Recent new initiatives, like the Global Alliance on Vaccines and Immunization (GAVI),which are gathering new sources of funding for vaccination, should be beneficial for vaccinology.

Evaluating the safety of combination vaccines.

The development of combination vaccines is important to facilitate protection of people from potentially life-threatening infectious diseases. As with all vaccines, the safety of these products is of critical importance. Although combination vaccines generally include components that have been studied and used previously, the possibility of new or more severe reactions arising from combining components cannot be dismissed. Controlled safety studies are needed for new combination vaccines to determine reliably whether risks are increased compared with administration of individual components. Such studies will generally be smaller than studies of vaccines with new immunogens, but the size of the study will depend on the types and rates of the reactions expected, given the vaccine's components, and on the level of increased risk that would be important to detect.

Strategies for development of combination vaccines.

The increasing complexity of the recommended childhood immunization schedule has resulted in the need for combination vaccines. Through an extensive review of the current literature, various strategies and issues related to the development of combination vaccines are discussed. Issues that should be considered when combining vaccine components include the current childhood immunization schedule, compatibility of components, availability of antigens for targeted diseases, safety, efficacy, immunogenicity and route of delivery. When choosing an appropriate combination of antigen(s)/serotype(s) for a global or national formulation, careful consideration must be made when selecting serotypes to combine depending on the market or area of use. It is important to know that potential interactions can involve other components of the vaccines, including buffers, adjuvants and preservatives. The Food and Drug Administration requires that the combination not only have immunogenicity comparable with those of the component vaccines, but that its safety profile be comparable with the most reactogenic component. The Food and Drug Administration also recommends that a test of noninferiority be performed, such that the combination performs similarly to the separate components with regard to antibody titers. Combination vaccines are critical to the success of vaccination programs, and each new combination must be carefully studied to ensure comparable safety and immunogenicity of the individual components.