Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated) and Haemophilus type b conjugate vaccine(Sanofi)

January 8, 2026 4:57 pm EST Rahway, N.J., Jan. 8, 2026 – At Merck, we share the same fundamental belief with health care providers and parents alike: every child deserves to grow up safe, healthy and able to thrive. Nothing is more important to us than the safety of our medicines and vaccines and the wellbeing of the people who rely on them. For many families today, diseases such as measles, polio and hepatitis B may feel like distant history. That progress exists because childhood vaccination has been remarkably successful. Decades of science-based immunization policy, supported by continuous safety monitoring and real-life evidence across millions of children, have helped protect communities. The U.S. child and adolescent immunization schedule has long reflected this rigorous approach. Vaccines are studied extensively in clinical trials using specific dosing regimens, and vaccinations are timed based on multiple scientific considerations, including when maternal antibodies wane, when children are most likely to be exposed to or susceptible to certain diseases, how immune systems respond at different ages and how healthcare providers can most effectively deliver protection. As the Department of Health and Human Services (HHS) makes changes to the immunization schedule, it is critical that changes are informed by comprehensive data and guided by experts in vaccinology, pediatrics, infectious diseases and epidemiology. International comparisons should also be evaluated in the proper context, recognizing differences in disease burden, healthcare infrastructure and population needs. Shared clinical decision-making plays an important role in healthcare, helping clinicians and families consider individual circumstances and risks. However, clear, evidence-based recommendations remain essential to support informed decisions and ensure that children and adolescents receive reliable protection against preventable diseases. As recent outbreaks in the U.S. have shown, sustained confidence in vaccination programs is critical to protecting individuals and communities. When vaccination rates decline, the consequences can be serious. Merck stands firmly behind an immunization framework grounded in rigorous science, strong regulatory processes and ongoing safety monitoring. We remain committed to working with public health partners to support policies that help protect children and adolescents, strengthen communities and preserve the progress achieved through immunization. Indication for M-M-R®II M-M-R®II is a vaccine indicated for active immunization for the prevention of measles, mumps, and rubella in individuals 12 months of age or older. The first dose of M-M-R®II is administered at 12 to 15 months of age and the second dose of M-M-R®II is administered at 4 to 6 years of age. Select Safety Information for M-M-R®II M-M-R®II is contraindicated in certain individuals, including those with: a history of hypersensitivity to any component of the vaccine, including gelatin; a history of anaphylactic reaction to neomycin; individuals who are immunodeficient or immunosuppressed due to disease or medical therapy; an active febrile illness; active untreated tuberculosis; or those who are pregnant or are planning to become pregnant within the next month. Due caution should be employed in administration of M-M-R®II to persons with: a history of febrile seizure or family history of febrile seizures; immediate-type hypersensitivity reactions to eggs; thrombocytopenia. Vaccination should be deferred in individuals with a family history of congenital or hereditary immunodeficiency until the individual’s immune status has been evaluated and the individual has been found to be immunocompetent. Immune globulins (IG) and other blood products should not be given concurrently with M-M-R®II. The ACIP has specific recommendations for intervals between administration of antibody-containing products and live virus vaccines. The following adverse reactions have been identified during both the subcutaneous and intramuscular use of M-M-R®II or its components in clinical trials or reported during post-approval use: fever, rash, and injection-site reactions. The following adverse reactions have been identified during the subcutaneous use of M-M-R®II or its components in clinical trials or reported during post-approval use: headache, dizziness, febrile convulsions, anaphylaxis and anaphylactoid reactions, arthritis, thrombocytopenia, encephalitis and encephalopathy. Dosage and Administration for M-M-R®II FOR INTRAMUSCULAR OR SUBCUTANEOUS USE ONLY. M-M-R®II vaccine can be administered concurrently with other live viral vaccines. If not given concurrently, M-M-R®II vaccine should be given one month before or one month after administration of other live viral vaccines to avoid potential for immune interference. Before administering M-M-R®II, please read the accompanying Prescribing Information. The Patient Information also is available. Indication for ProQuad® ProQuad is a vaccine indicated for active immunization for the prevention of measles, mumps, rubella, and varicella in children 12 months through 12 years of age. VARIVAX is a vaccine indicated for active immunization for the prevention of varicella in individuals 12 months of age or older. M-M-R®II is indicated for active immunization for the prevention of measles, mumps, and rubella in individuals 12 months of age or older. Select Safety Information for ProQuad Hypersensitivity: ProQuad, M-M-R®II (Measles, Mumps, and Rubella Virus Vaccine Live), and VARIVAX® (Varicella Virus Vaccine Live)are contraindicated in patients with a history of anaphylactic reaction or hypersensitivity to any component of the vaccine (including gelatin or neomycin) or to a prior dose of measles, mumps, rubella, or varicella-containing vaccine. Use caution when administering ProQuad and M‑M‑R®II to individuals with anaphylaxis or immediate hypersensitivity to eggs. ProQuad, M-M-R®II, and VARIVAXare contraindicated in certain individuals, including those with: immunodeficiency or who are immunosuppressed; an active febrile illness; untreated tuberculosis. Pregnancy: ProQuad, M-M-R®II, and VARIVAX are contraindicated for use in pregnant women. Do not administer ProQuad or VARIVAX to individuals who are planning to become pregnant in the next 3 months. Do not administer M-M-R®II to individuals who are planning to become pregnant in the next month. Febrile Seizures: Administration of ProQuad (dose 1) to children 12 to 23 months old who have not been previously vaccinated against measles, mumps, rubella, or varicella, nor had a history of the wild-type infections, is associated with higher rates of fever and febrile seizures at 5 to 12 days after vaccination when compared to children vaccinated with a first dose of both M-M-R®II and VARIVAX administered concomitantly. Febrile Seizures: Use caution when administering ProQuad and M-M-R®II to individuals with a history of febrile seizures. Family History of Immunodeficiency: Vaccination with ProQuad, M-M-R®II, and VARIVAX should be deferred in individuals with a family history of congenital or hereditary immunodeficiency until the individual’s immune status has been evaluated and the individual has been found to be immunocompetent. Thrombocytopenia: Transient thrombocytopenia has been reported within 4-6 weeks following vaccination with measles, mumps, and rubella vaccine. Carefully evaluate the potential risk and benefit of vaccination in children with thrombocytopenia or in those who experienced thrombocytopenia after vaccination with a previous dose of a measles, mumps, and rubella-containing vaccine. Varicella Transmission and Precautions: Advise vaccinees administered ProQuad or VARIVAX to avoid: close contact with high-risk individuals susceptible to varicella for up to 6 weeks following vaccination since transmission of varicella vaccine virus to susceptible contacts has been reported. Varicella vaccine virus transmission may occur between vaccine recipients and contacts susceptible to varicella including healthy individuals. Immune Globulins and Other Blood Products: Immune Globulins and other blood products should not be given concomitantly with ProQuad, M-M-R®II, or VARIVAX. Use of Salicylates: Avoid use of salicylates in children and adolescents administered ProQuad or VARIVAX for 6 weeks following vaccination due to the association of Reye Syndrome with salicylate therapy and wild-type varicella infection. Adverse Events: The following adverse events have been reported for both subcutaneous and intramuscular injections of ProQuad, M-M-R®II, and VARIVAX: fever, injection-site reactions (pain/tenderness/soreness, erythema, and swelling); and rash on the body or at the injection site. Additionally, irritability has been reported for the subcutaneous injections of ProQuad, M-M-R®II, and VARIVAX. ProQuad Systemic Vaccine-Related Adverse Events: Systemic vaccine-related adverse events that were reported at a significantly greater rate in recipients of subcutaneous ProQuad than in recipients of the component vaccines administered concomitantly were fever and measles-like rash. VARIVAX Dose-related Adverse Events: In a clinical trial involving children who received 2 doses of VARIVAX 3 months apart, the incidence of injection-site clinical complaints observed in the first 4 days following vaccination was slightly higher post-dose 2 (overall incidence 25.4%) than post-dose 1 (overall incidence 21.7%), whereas the incidence of systemic clinical complaints in the 42-day follow-up period was lower post-dose 2 (66.3%) than post-dose 1 (85.8%). Concomitant Vaccines With ProQuad: ProQuad may be administered concomitantly with diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed (DTaP), Haemophilus influenzae type b conjugate (meningococcal protein conjugate) and hepatitis B (recombinant) vaccine. It may also be administered concomitantly with pneumococcal 7-valent conjugate vaccine and/or hepatitis A vaccine (inactivated) at separate injection sites. Concomitant Vaccines With VARIVAX: VARIVAX can be administered with other live viral vaccines. If not given concurrently, at least 1 month should elapse between a dose of a live attenuated measles virus-containing vaccine and a dose of VARIVAX. In children, at least 3 months should elapse between administration of 2 doses of a live attenuated varicella virus-containing vaccine. Tuberculin Testing: If a tuberculin test is to be done with M-M-R®II and ProQuad, it should be administered either any time before, simultaneously with, or at least 4 to 6 weeks after vaccination. With VARIVAX, tuberculin testing may be performed before the vaccine is administered or at least 4 weeks following vaccination. Additional M-M-R®II Precautions: Additional adverse reactions, which have been reported without regard to causality, include febrile convulsions, arthritis, thrombocytopenia, anaphylaxis, anaphylactoid reactions, arthritis, encephalitis and encephalopathy in their diverse clinical presentations. Additional VARIVAX Precautions: It is not known if varicella vaccine virus is excreted in human milk. A boost in antibody levels has been observed in vaccinees following exposure to wild-type varicella, which could account for the apparent long-term persistence of antibody levels in studies. The duration of protection from varicella infection after vaccination is unknown. ProQuad/VARIVAX and Herpes Zoster: The long-term effect of VARIVAX on the incidence of herpes zoster, particularly in those vaccinees exposed to wild-type varicella, is unknown at present. Efficacy: Vaccination with ProQuad, VARIVAX, or M-M-R®II may not result in protection in 100% of vaccinees. Dosage and Administration for ProQuad ProQuad: Each dose of ProQuad is approximately 0.5 mL and is administered intramuscularly or subcutaneously. At least 1 month should elapse between a dose of a measles-containing vaccine such as M-M-R®II and a dose of ProQuad. At least 3 months should elapse between a dose of varicella-containing vaccine and ProQuad. VARIVAX: Each dose is approximately 0.5 mL and is administered intramuscularly or subcutaneously. The first dose is administered at 12 to 15 months of age. The second dose is administered at 4 to 6 years of age. There should be a minimum interval of 3 months between doses. 12 months to 12 years of age: If a second dose is administered, there should be a minimum interval of 3 months between doses. Adolescents (≥13 years of age) and Adults: 2 doses, to be administered with aminimum interval of 4 weeks between doses. The first dose is administered at 12 to 15 months of age. The second dose is administered at 4 to 6 years of age. There should be a minimum interval of 3 months between doses. 12 months to 12 years of age: If a second dose is administered, there should be a minimum interval of 3 months between doses. Adolescents (≥13 years of age) and Adults: 2 doses, to be administered with aminimum interval of 4 weeks between doses. M-M-R®II: The dose for any age is approximately 0.5 mL administered intramuscularly or subcutaneously. The recommended age for primary vaccination is 12 to 15 months and the second dose should be given at 4 to 6 years of age. The recommended age for primary vaccination is 12 to 15 months and the second dose should be given at 4 to 6 years of age. Before administering VARIVAX (Varicella Virus Vaccine Live), M-M-R®II (Measles, Mumps, and Rubella Virus Vaccine Live), or ProQuad (Measles, Mumps, Rubella and Varicella Virus Vaccine Live), please read the accompanying Prescribing Information. The Patient Information also is available for VARIVAX , M-M-R®II , and ProQuad. Indication for RECOMBIVAX HB® RECOMBIVAX HB is indicated for prevention of infection caused by all known subtypes of hepatitis B virus. RECOMBIVAX HB is approved for use in individuals of all ages. RECOMBIVAX HB Dialysis Formulation is approved for use in adult predialysis and dialysis patients 18 years of age and older. Select Safety Imformation for RECOMBIVAX HB Do not administer RECOMBIVAX HB to individuals with a history of severe allergic or hypersensitivity reactions (eg, anaphylaxis) after a previous dose of any hepatitis B-containing vaccine or to any component of RECOMBIVAX HB, including yeast. The vial stopper and the syringe plunger stopper and tip cap contain dry natural latex rubber, which may cause allergic reactions in latex-sensitive individuals. Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including RECOMBIVAX HB, to infants born prematurely should be based on consideration of the individual infant’s medical status and the potential benefits and possible risks of vaccination. For RECOMBIVAX HB, this assessment should include consideration of the mother’s hepatitis B antigen status and high probability of maternal transmission of hepatitis B virus to infants born to mothers who are HBsAg positive if vaccination is delayed. Hepatitis B vaccination should be delayed until 1 month of age or hospital discharge in infants weighing <2000 g if the mother is documented to be HBsAg negative at the time of the infant’s birth. Infants weighing <2000 g born to HBsAg positive or HBsAg unknown mothers should receive vaccine and hepatitis B immune globulin (HBIG) in accordance with ACIP recommendations if HBsAg status cannot be determined. Hepatitis B virus has a long incubation period. RECOMBIVAX HB may not prevent hepatitis B infection in individuals who have an unrecognized hepatitis B infection at the time of vaccination. Vaccination with RECOMBIVAX HB may not protect all individuals. In healthy infants and children (up to 10 years of age), injection site reactions and systemic adverse reactions were reported following 0.2% and 10.4% of the injections, respectively. The most frequently reported systemic adverse reactions (>1% injections), in decreasing order of frequency, were irritability, fever, diarrhea, fatigue/weakness, diminished appetite, and rhinitis. In a study that compared the 3-dose regimen (5 mcg) with the 2-dose regimen (10 mcg) of RECOMBIVAX HB in adolescents, the overall frequency of adverse reactions was generally similar. In a group of studies involving healthy adults, injection site reactions and systemic adverse reactions were reported following 17% and 15% of the injections, respectively. The following adverse reactions were reported (≥1% of injections) injection site reactions, fatigue/weakness, headache, fever, malaise, nausea, diarrhea, pharyngitis, and upper respiratory infection. Additional adverse reactions have been reported with the use of the marketed vaccine. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to a vaccine exposure. Use in Special Populations Pregnancy There are no adequate and well-controlled studies designed to evaluate RECOMBIVAX HB in pregnant women. Available post-approval data do not suggest an increased risk of miscarriage or major birth defects in women who received RECOMBIVAX HB during pregnancy. Nursing Mothers Data are not available to assess the effects of RECOMBIVAX HB on the breastfed infant or on milk productions/excretion. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RECOMBIVAX HB and any potential adverse effects on the breastfed child from RECOMBIVAX HB or from the underlying maternal condition. Pediatric Use The safety and effectiveness of RECOMBIVAX HB Dialysis Formulation in children have not been established. Geriatric Use Clinical studies of RECOMBIVAX HB did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, in later studies it has been shown that a diminished antibody response can be expected in persons older than 60 years of age. In addition, the responses to these vaccines may be lower if the vaccine is administered as a buttock injection. Predialysis and Dialysis Patients Predialysis and dialysis adult patients respond less well to hepatitis B vaccines than do healthy individuals; however, vaccination of adult patients early in the course of their renal disease produces higher seroconversion rates than vaccination after dialysis has been initiated. Known or Presumed Exposure to HBsAg Refer to recommendations of the Advisory Committee on Immunization Practices (ACIP) and to the package insert for hepatitis B immune globulin (HBIG) for management of persons with known or presumed exposure to the hepatitis B virus (eg, neonates born of infected mothers or persons who experienced percutaneous or permucosal exposure to the virus). When recommended, administer RECOMBIVAX HB and HBIG intramuscularly at separate sites (eg, opposite anterolateral thighs for exposed neonates) as soon as possible after exposure. Dosage and Administration for RECOMBIVAX HB The vaccination regimen for RECOMBIVAX HB for persons from birth through 19 years of age consists of a series of 3 doses (0.5 mL each) given on a 0-, 1-, and 6-month schedule. The vaccination regimen for RECOMBIVAX HB for adolescents 11 through 15 years of age consists of a series of 3 doses (0.5 mL each) given on a 0-, 1-, and 6-month schedule, or a series of 2 doses (1.0 mL each) on a 0- and 4- to 6-month schedule. The vaccination regimen for RECOMBIVAX HB for persons 20 years of age and older consists of a series of 3 doses (1.0 mL each) given on a 0-, 1-, and 6-month schedule. The deltoid muscle is the preferred site for intramuscular injection for adults, adolescents, and children 1 year of age and older whose deltoid is large enough for intramuscular injection. The anterolateral aspect of the thigh is the preferred site for intramuscular injection for infants younger than 1 year of age. RECOMBIVAX HB should not be administered in the gluteal region, as injections given in the buttocks have resulted in lower seroconversion rates than expected. Consider subcutaneous administration only in persons who are at risk of hemorrhage following intramuscular injections. Predialysis and Dialysis Adult Patients: The vaccination regimen for RECOMBIVAX HB Dialysis Formulation for adults on predialysis and dialysis consists of a series of 3 doses (1.0 mL each) given on a 0-, 1-, and 6-month schedule. Consider a booster dose or revaccination with RECOMBIVAX HB Dialysis Formulation (blue color code) in predialysis/dialysis patients if the anti-HBs level is less than 10 mIU/mL at 1 to 2 months after the third dose. The duration of the protective effect on RECOMBIVAX HB in healthy vaccinees is unknown at present and the need for booster doses is not yet defined. RECOMBIVAX HB should be administered as soon as possible after being removed from refrigeration. Before administering RECOMBIVAX HB, please read the accompanying Prescribing Information. Indication for VAXELIS® VAXELIS is a vaccine indicated for active immunization to prevent diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, and invasive disease due to Haemophilus influenzaetype b. VAXELIS is approved for use as a 3-dose series in children 6 weeks through 4 years of age (prior to the 5th birthday). Select Safety Information for VAXELIS VAXELIS is contraindicated in children with a history of severe allergic reaction (eg, anaphylaxis) to a previous dose of VAXELIS, any ingredient of VAXELIS, or any other diphtheria toxoid, tetanus toxoid, pertussis-containing vaccine, inactivated poliovirus vaccine, hepatitis B vaccine, or H. influenzaetype b vaccine. Do not administer VAXELIS to anyone with a history of encephalopathy (e.g., coma, decreased level of consciousness, prolonged seizures), within 7 days of a pertussis-containing vaccine that is not attributable to another identifiable cause. Do not administer VAXELIS to anyone with a history of progressive neurologic disorder until a treatment regimen has been established and the condition has stabilized. Vaccination with VAXELIS may not protect all individuals. Carefully consider benefits and risks before administering VAXELIS to persons with a history of: fever of ≥40.5°C (≥105°F), hypotonic-hyporesponsive episode (HHE) or persistent, inconsolable crying lasting ≥3 hours within 48 hours after a previous pertussis-containing vaccine. seizures within 3 days after a previous pertussis-containing vaccine. If Guillain-Barré syndrome occurred within 6 weeks of receipt of a prior vaccine containing tetanus toxoid, the risk for Guillain-Barré syndrome may be increased following VAXELIS. Apnea following intramuscular vaccination has been observed in some infants born prematurely. The decision about when to administer an intramuscular vaccine, including VAXELIS, to an infant born prematurely should be based on considerations of the individual infant’s medical status and the potential benefits and possible risks of vaccination. Urine antigen detection may not have definitive diagnostic value in suspected H. influenzatype b disease following vaccination with VAXELIS. The solicited adverse reactions following any dose were irritability (≥55%), crying (≥45%), injection site pain (≥44%), somnolence (≥40%), injection site erythema (≥25%), decreased appetite (≥23%), fever ≥38.0°C (≥19%), injection site swelling (≥18%), and vomiting (≥9%). Dosage and Administration for VAXELIS The 3-dose immunization series consists of a 0.5 mL intramuscular injection, administered at 2, 4, and 6 months of age. A 3-dose series of VAXELIS does not constitute a primary immunization series against pertussis; an additional dose of pertussis-containing vaccine is needed to complete the primary series. Before administering VAXELIS, please read the accompanying Prescribing Information. The Patient Information also is available. About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. 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The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2024 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov). 1 VAXELIS™ is the result of the U.S.-based business joint-partnership (MCM) created in 1991 between Merck & Co., Inc., Connaught Laboratories and Pasteur Mérieux Serums & Vaccins, the latter two now known as Sanofi Pasteur, the vaccines unit of Sanofi. 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▲2004页2025 WCLC摘要集免费领取！摘要：百日咳作为一种严重的呼吸道传染病，虽在全细胞疫苗（wP）问世后发病率大幅下降，但随着无细胞疫苗（aP）的广泛应用，其发病率却出现回升。本文从百日咳疫苗的发展现状出发，详细介绍了现有疫苗的抗原成分、联合疫苗的种类，深入分析了疫苗效果不佳的原因，重点探讨了新型佐剂在提升疫苗免疫效果方面的作用，包括不同类型佐剂的作用机制、临床前研究成果等，同时还涉及疫苗稳定性及未来发展方向，为新一代百日咳疫苗的研发提供全面且易懂的参考。 一、百日咳与疫苗的 “前世今生” 百日咳是由百日咳杆菌引起的一种严重传染性呼吸道疾病，对婴儿、儿童和成人都有威胁。回顾历史，1948 年全细胞百日咳（wP）疫苗的研发是一个重要里程碑。在这之前，1940 年百日咳的发病率为每 10 万人 157 例，而到了 1973 年，这一数字降至每 10 万人 1 例，足见 wP 疫苗的显著效果。 然而，wP 疫苗虽有效，但安全性方面存在不足。相比之下，无细胞百日咳（aP）疫苗凭借更好的安全记录逐渐占据主导地位。但近年来，百日咳疫情的反弹令人担忧。2020 - 2022 年期间，由于新冠疫情期间广泛的公共卫生措施，百日咳报告病例数和发病率有所下降，2022 年全球报告病例为 62646 例。但 2023 年，全球百日咳病例数增至 158910 例，截至 2024 年 11 月 30 日，美国报告的百日咳病例数是 2023 年同期的六倍多。 百日咳卷土重来的原因众多。首先是疫苗覆盖率存在地区差异；其次，自然感染或接种疫苗获得的免疫力会随时间逐渐下降；再者，一些百日咳杆菌菌株不再产生某些疫苗抗原（如 PRN），这使其在接种aP疫苗的人群中更易存活；另外，疫苗中缺乏像腺苷酸环化酶毒素这样能诱导保护性免疫反应的毒力因子，且某些抗原（如丝状血凝素）的免疫调节活性有限，会促进免疫抑制性细胞因子的产生等。还有一个关键因素是，aP 疫苗替代 wP 疫苗后，无法提供最佳的免疫增强效果和长期保护，这与两种疫苗使用铝佐剂所引发的不同免疫刺激密切相关。二、无细胞百日咳疫苗的抗原成分 百日咳杆菌是一种感染呼吸道的人类病原体，在宿主的黏膜表面会产生多种毒力因子，这些毒力因子常被纳入 aP 疫苗，在预防百日咳感染中发挥关键作用。（一）百日咳毒素（PT） PT 是一种分泌到细胞外的毒素，也是百日咳杆菌的关键毒力因子，在百日咳的发病机制中处于核心地位，被广泛认为是导致百日咳临床症状的主要因素。疫苗诱导产生的血清中 PT 特异性 IgG 水平与对百日咳的保护作用密切相关，因此 PT 是目前所有 aP 疫苗中最具代表性的抗原。 PT 遵循经典的细菌毒素 A/B 模型，A 组分具有酶活性，B 组分负责与靶细胞受体结合。在小鼠鼻内感染模型中，PT 会特异性地靶向气道驻留巨噬细胞，促进百日咳杆菌在呼吸道的早期定植，同时还会抑制中性粒细胞的募集，帮助细菌逃避早期免疫攻击。多项研究表明，抗 PT 抗体能有效保护小鼠免受脑内（IC）攻击。1997 年，丹麦批准了一种含过氧化氢灭活 PT 的单组分 aP 疫苗，该疫苗用于婴儿初次接种（DTaP - IPV）和儿童加强剂量接种（TdaP 和 TdaP - IPV），尽管仅以 PT 为唯一抗原，但丹麦的百日咳负担与使用多组分 aP 疫苗的邻国相当。（二）丝状血凝素（FHA） 与细菌毒素 PT 不同，FHA 主要参与细菌对气管上皮细胞的黏附，它是一种螺旋状蛋白质，可释放到细胞外环境中。FHA 内的多个结构域有助于其与巨噬细胞和呼吸道上皮细胞结合。 木村等人的研究显示，通过腹腔或肌肉注射 FHA 免疫小鼠后，小鼠会产生 FHA 特异性抗体，气管和肺部的细菌定植量减少。在一项人体研究中，日本的一种含 PT 和 FHA 的双组分疫苗在 3 年多的时间里提供了比单组分 PT 疫苗更好的长期保护。瑞典的一项临床试验评估了单组分（仅 PT，JNIH - 7）和双组分（PT + FHA，JNIH - 6）疫苗在 5 - 11 个月大婴儿中的疗效。在第二次接种后 30 天开始的 15 个月随访中，单组分疫苗组有 27 人确诊百日咳，双组分疫苗组有 18 人，估计保护效力分别为 54% 和 69%。重要的是，进一步的随访表明，与单独使用 PT 相比，加入 FHA 能显著降低百日咳杆菌感染的发生率。（三）百日咳黏附素（PRN） PRN 是一种与细菌表面相关的蛋白质，通过其精氨酸 - 甘氨酸 - 天冬氨酸基序和富含脯氨酸的结构域促进对气管上皮细胞的吸附。在小鼠模型中，PRN 通过抑制中性粒细胞介导的清除作用促进发病，并引发炎症，从而增加细菌的脱落和传播。研究表明，用 PRN 免疫可抑制肺部细菌增殖，有助于感染的早期清除。（四）菌毛（FIM） FIM 是细菌表面表达的丝状聚集蛋白质结构，作为黏附素促进细菌与宿主组织的黏附。主要有两种血清型，FIM2 和 FIM3，代表不同的菌毛结构。 Holuboval 等人证明，FHA 和 FIM 介导的共黏附对于鼻定植、分泌物诱导、脱落以及随后的宿主间传播至关重要。小鼠研究显示，增加 aP 疫苗中 FIM 的含量可增强保护作用，且不会增加反应原性。瑞典的临床试验比较了双组分、三组分和五组分 aP 疫苗与全细胞百日咳（wP）疫苗的效果，发现双组分疫苗的效力显著较低。五组分、三组分 aP 疫苗以及 wP 疫苗在预防至少持续 21 天的阵发性咳嗽的培养确诊百日咳方面具有相当的保护作用，但三组分疫苗对轻度疾病的保护作用相对较弱，这表明 FIM 在减少感染和传播方面有一定作用。 图 1：百日咳杆菌及其毒力因子的示意图百日咳杆菌产生多种毒力因子，包括百日咳毒素（PT）、腺苷酸环化酶毒素（ACT）、气管细胞毒素（TCT）、皮肤坏死毒素（DNT）、丝状血凝素（FHA）、菌毛（FIM）、百日咳黏附素（PRN）、博德特氏菌抗杀伤抗原（BrkA）和气管定植因子（TCF）。三、无细胞百日咳联合疫苗 这些百日咳抗原通常与破伤风和白喉毒素联合使用。FDA 批准的人类联合疫苗包括用于儿童的 INFANRIX（葛兰素史克生物制品公司）和 DAPTACEL（赛诺菲巴斯德公司），以及用于青少年和成人的 BOOSTRIX（葛兰素史克生物制品公司）和 Adacel（赛诺菲巴斯德公司）。青少年和成人疫苗中百日咳抗原和白喉类毒素的含量低于儿童疫苗，而破伤风类毒素的含量大致相同。 DAPTACEL（赛诺菲巴斯德公司）和 Adacel（赛诺菲巴斯德公司）是五组分疫苗制剂，含有磷酸铝佐剂；而 INFANRIX（葛兰素史克生物制品公司）和 BOOSTRIX（葛兰素史克生物制品公司）是三组分疫苗制剂（不含 2 型和 3 型 FIM）。Susanna Esposito 和 Nicola Principi 对 Greco 和 Gustafsson 的研究总结指出，三组分和五组分疫苗的效力似乎相似。然而，Carvalho 等人报告称，接种三抗原（aP3）aP 疫苗的儿童比接种 wP 疫苗的儿童更易感染百日咳，而在初次接种中接种五抗原（aP5）aP 疫苗的儿童感染百日咳的风险与接种 wP 疫苗的儿童相似。 除了传统的破伤风 - 白喉 - 百日咳疫苗外，联合疫苗还可能包含其他抗原。例如，FDA 批准的疫苗 KINRIX（葛兰素史克生物制品公司）和 Quadracel（赛诺菲巴斯德公司）与脊髓灰质炎病毒抗原联合使用，分别使用氢氧化铝佐剂和磷酸铝佐剂。PEDIARIX（葛兰素史克生物制品公司）与乙肝抗原和脊髓灰质炎病毒抗原联合使用，白喉和破伤风类毒素以及百日咳抗原（PT、FHA 和 PRN）吸附在氢氧化铝上，乙肝成分吸附在磷酸铝上。为预防 B 型流感嗜血杆菌（Hib）引起的侵袭性疾病，VAXELIS（MCM 疫苗公司）和 Pentacel（赛诺菲巴斯德公司）中添加了蛋白质结合的多核糖基核糖醇磷酸（PRP）以增强免疫原性。PRP 是侵袭性 Hib 疾病的主要毒力因子，是一种具有良好保护效果的高度免疫原性抗原。VAXELIS 中包含 PRP 与 B 群脑膜炎奈瑟菌外膜蛋白复合物（OMPC）的共价结合物，吸附在无定形羟基磷酸铝硫酸盐上，乙肝也吸附在无定形羟基磷酸铝硫酸盐上，而白喉和破伤风类毒素以及百日咳抗原分别吸附在磷酸铝上。Pentacel 中包含 PRP 与破伤风类毒素的共价结合物，以及吸附在磷酸铝上的白喉、破伤风类毒素和百日咳抗原。 表 1：FDA 批准的含百日咳抗原的人用疫苗 四、无细胞百日咳联合疫苗的佐剂 为增强免疫原性，aP 疫苗通常会添加佐剂。佐剂用于灭活疫苗、亚单位疫苗和重组疫苗中，以刺激先天和适应性免疫反应，从而获得最佳且持久的免疫原性。 过去人们认为百日咳杆菌是一种特殊的胞外病原体，含铝盐佐剂的 aP 疫苗诱导的强大体液免疫足以预防百日咳杆菌感染。但后来发现，百日咳杆菌能感染并存活于人类肺泡巨噬细胞和小鼠支气管肺泡灌洗液细胞中，细胞免疫在预防百日咳中可能起着至关重要的作用。Mills 等人发现，即使没有可检测到的血清抗体反应，CD4 + T 细胞也能介导细菌清除，且自然百日咳感染诱导的主要 T 细胞是分泌 IL - 2 和 IFN - γ 的 CD4 + T 细胞，IFN - γ 可激活巨噬细胞以清除细胞内的百日咳杆菌。 在小鼠中，Th1 细胞介导的细胞免疫反应对于抵抗呼吸道感染引起的百日咳至关重要（图 2）。Ross 等人在自然感染百日咳的小鼠肺部发现了大量百日咳杆菌特异性 Th17 细胞，他们发现过继转移百日咳杆菌特异性 Th1 或 Th17 细胞能有效保护小鼠免受百日咳杆菌感染，尤其是当这两种细胞群一起转移时。Th1 和 Th17 免疫都有助于小鼠对百日咳杆菌感染的自然免疫（图 2）。wP 疫苗也能刺激 Th1 和 Th17 细胞，在小鼠中提供由 IFN - γ 介导的保护性免疫，IL - 17A 也有一定作用，尽管程度较轻。然而，IL - 17A 在 aP 疫苗诱导的保护性免疫中很重要，它通过募集巨噬细胞和中性粒细胞来增强肺部百日咳杆菌的清除。 在狒狒模型中也证实了 Th1 和 Th17 反应的重要性，能刺激 Th1 和 Th17 记忆反应的 wP 疫苗能更快地清除感染。与在小鼠中诱导 Th2/Th17 免疫反应不同，在狒狒中诱导 Th1/Th2 反应的 aP 疫苗清除感染较慢，且无法有效预防百日咳杆菌在呼吸道的定植和传播。这是因为 wP 疫苗含有大量抗原和潜在佐剂，而 aP 疫苗仅使用单一佐剂和有限的抗原组合，从而引发不同且更局限的免疫反应，这与近年来百日咳的复发有关。因此，除了铝盐佐剂外，旨在诱导 Th1 和 Th17 反应的新型佐剂，如 MF59、AS04、AS01、CpG ODN、Poly（I:C）、TLR7 激动剂、脂蛋白、脂质体等，在新型百日咳疫苗中也显示出发展潜力（图 3），且在临床前研究中取得了一定成果（表 2）。 图 2：小鼠对百日咳杆菌自然免疫的机制示意图百日咳杆菌初次呼吸道感染后，局部树突状细胞（DCs）捕获百日咳杆菌抗原，迁移至引流淋巴结，在特定细胞因子的作用下刺激初始 CD4 + T 细胞分化为 Th1 和 Th17 细胞。分泌 IFN - γ 的 Th1 细胞激活肺泡巨噬细胞，清除呼吸道中的百日咳杆菌。Th17 细胞释放的 IL - 17 有助于中性粒细胞募集到肺部。初始 CD4 + T 细胞也可分化为效应记忆 T（TEM）细胞，迁移至鼻组织和肺部，并作为组织驻留记忆 T（TRM）细胞保留在那里。再次感染时，IL - 17 + CD4 + TRM 细胞扩增并募集唾液酸结合 Ig 样凝集素（Siglec）- F + 中性粒细胞，这些中性粒细胞在鼻咽部形成中性粒细胞胞外陷阱（NETs）（NETosis）的潜力更高，有助于细菌清除。B 细胞在 DCs 和辅助性 T 细胞的刺激下分化为浆细胞并分泌抗体。分泌的二聚体 IgA 与 polymeric 免疫球蛋白受体结合，以分泌型 IgA 的形式释放到受感染的呼吸道组织中。 图 3：百日咳疫苗中具有免疫潜力的佐剂多种佐剂可用于百日咳疫苗，包括明矾、脂质体、MF59、CpG ODN、TLR7 激动剂、Poly（I:C）、脂蛋白、AS04 等。（一）铝盐佐剂 铝盐佐剂被选用于百日咳疫苗，是因为其历史悠久、符合监管要求，且在联合疫苗的应用中具有后勤优势。传统上认为，铝盐佐剂具有 depot 效应，能在注射部位持续释放抗原。铝盐与抗原的结合可促进抗原呈递细胞（APCs）的摄取和呈递。此外，铝佐剂还能激活 NLRP3 炎症小体，促进 IL - 1β 和 IL - 18 的产生。铝佐剂可促进抗体产生和 Th2 反应，这与体液免疫有关。 研究表明，铝佐剂的类型会影响免疫反应，氢氧化铝和磷酸铝均常被用于增强免疫反应。在无细胞百日咳疫苗中，三组分疫苗 InfanrixTM 或 PediarixTM（抗原吸附在氢氧化铝上）以及五组分疫苗 PediacelTM 或 PentacelTM（抗原吸附在磷酸铝上）被广泛使用（表 1）。Morel 等人比较了含有 PT、PRN 和 FHA 三种抗原的 DTaP3 与 DTaP5 的效果，发现 DTaP3 比 DTaP5 制剂提供更好的保护和持久性。PediacelTM 在启动体液反应方面不如 InfanrixTM 有效，这可能与佐剂类型有关。疫苗抗原与磷酸铝的结合较松散，会影响抗原反应。Denoël 等人还证明，PRN 更容易从磷酸铝佐剂上解吸，影响 PRN 抗原反应和小鼠肺部清除活性。这表明制剂工艺在刺激免疫反应中很重要。 在吸附疫苗的生产中，除了铝佐剂的类型外，多种因素会影响抗原与佐剂的吸附。溶液的 pH 值决定了被吸附抗原和佐剂的表面电荷，当 pH 值介于佐剂和抗原的等电点之间时，可通过静电相互作用发生吸附。溶液中离子的存在，如磷酸盐和柠檬酸盐，容易导致抗原解吸。对于 aP 疫苗这类多抗原吸附疫苗，吸附顺序（如顺序吸附、竞争性吸附和单独吸附）也会影响吸附行为。（二）TLR9 激动剂 含胞嘧啶-硫代磷酸酯-鸟嘌呤（CpG）基序的寡脱氧核苷酸（ODN）可通过 TLR9 直接刺激抗原呈递细胞，从而加速免疫反应。CpG ODN 作为一种强效佐剂，可诱导 Th1 反应，促进细胞毒性 T 淋巴细胞（CTL）的大量产生和 IFN-γ 的分泌，增强对抗原的特异性体液和细胞免疫反应。 CpG ODN 1018 被批准用于乙肝疫苗 HEPLISAV-B，CpG ODN 2006 被批准用于炭疽疫苗 CYFENDUS。Sugai等人将 CpG-ODN 加入白喉-百日咳-破伤风（DPT）疫苗中，评估明矾和 CpG-ODN 联合佐剂的免疫效果。接种含 CpG-ODN 的 DPT 疫苗（DPT-明矾/ODN）的小鼠血清总 IgE 水平显著降低，血清抗 PT 特异性 IgG2a 滴度升高。此外，还研究了接种后对口服卵清蛋白（OVA）的抗体反应，在接受 DPT-明矾/ODN 的组中，血清中 OVA 特异性 IgE 的产生减少。 DeJong 等人将 CpG 1018 添加到 Tdap 中，诱导更多的 Th1 抗体，增强下呼吸道的保护作用和细菌清除率。此外，无论百日咳杆菌菌株是否表达 PRN，Tdap + CpG 1018 都能提供保护，缓解了人们对 PRN 突变体可能抵抗疫苗介导的免疫反应的担忧。Dynavax 进行的 1 期试验评估了试验性破伤风/白喉/无细胞百日咳疫苗与 CpG 1018 佐剂联合在成人和青少年中的安全性和免疫原性，结果显示安全性和耐受性良好。Tdap-1018 3000μg 诱导的免疫反应与目前市售的成人和青少年用 Boostrix 相当或更强。 尽管 CpG 未用于特殊人群的百日咳疫苗，但与三剂铝佐剂乙肝疫苗相比，两剂含 CPG1018 的乙肝疫苗在老年人中产生更高的血清保护水平，且在怀孕期间未观察到不良妊娠结局增加。（三）TLR7 激动剂 TLR7 激动剂具有佐剂活性，可在多种传染病中诱导 Th1/Th17 反应。小分子 TLR7 激动剂与铝佐剂联合使用可减轻全身炎症，减少细胞因子释放到血液中，提高其作为佐剂的安全性。 Misiak 等人将 TLR7a（Toll 样受体 7 激动剂）添加到含明矾佐剂的 aP 疫苗中，可将其从诱导 Th2 反应的疫苗转变为诱导 Th1/Th17 反应的疫苗，从而具有更强的保护能力。明矾 - TLR7a 佐剂疫苗比明矾佐剂疫苗更有效，可促进 Th1 极化反应，且抗原剂量显著降低。铝 - TLR7a 佐剂增加了 PT 中和抗体的产生，抑制了 FHA 与肺上皮的结合，并增强了小鼠气溶胶攻击模型的保护性免疫。（四）TLR4 激动剂 TLR4 激动剂 LPS 是百日咳杆菌外膜的天然成分，存在于 wP 疫苗中，可作为天然佐剂帮助诱导保护性免疫。3'- O - 脱酰基单磷酰脂质 A（MPL）是一种脱毒的 LPS 衍生物，可与 TLR4 结合并促进先天免疫反应。MPL 与氢氧化铝佐剂的组合形成 AS04，已被批准用于乙肝病毒疫苗 FENDRIX 和人乳头瘤病毒疫苗 CERVARIX。 Geurtsen 等人使用两种 LPS 类似物（MPL 和脑膜炎奈瑟菌 LpxL2LPS）替代 DTaP 疫苗中的铝佐剂，发现将 LPS 类似物纳入疫苗可减少肺部定植，诱导更高的 Ptx 特异性 IgG 水平，使反应更具 Th1 型反应特征，并减少Ⅰ型超敏反应。Agnolon 等人评估了乳剂佐剂 MF59 和 TLR4 激动剂单磷酰脂质 A（MPLA）与氢氧化铝（明矾）的组合，添加 MPLA 和 MF59 可增加 IgG2a 抗体滴度，刺激 IgG2a/Th1 反应，增强 DT 的中和活性，并阻断 FHA 与人类肺上皮细胞的结合。 Mitchell 等人认为，百日咳杆菌的 TLR4 刺激功能是 wP 疫苗转变为内毒素含量极低的 aP 疫苗时丢失的特性之一，而 TLR4 对免疫至关重要。MPL 具有改良百日咳疫苗可能需要的佐剂特性，包括抑制反应性、提供更持久的免疫力和减少 Th2 偏向。此外，AS04 具有良好的安全性，在受孕前 60 天至分娩期间接种 AS04 - HPV - 16/18 疫苗不会增加致畸风险，AS04 佐剂非常适合用于百日咳疫苗。（五）TLR2 激动剂 百日咳杆菌表达多种脂蛋白，作为 TLR2 激动剂，同时也具有抗原特性。Dunne 等人从百日咳杆菌中纯化出一种新型 TLR2 激活脂蛋白 BP1569，表明相应的合成脂肽 LP1569 能有效刺激免疫系统，具有佐剂特性，可诱导 Th1 和 Th17 反应。在预防小鼠百日咳杆菌定植方面，它比铝基疫苗更有效。（六）MF59 MF59 由角鲨烯、聚山梨酯 80、山梨糖醇三油酸酯和脱水柠檬酸三钠组成，已在 30 个国家的许可产品中使用，主要用于流感疫苗。MF59 促进抗原在注射部位的吸收和免疫细胞的募集，增强抗原向引流淋巴结的运输，并加强 Th1 和 Th2 的免疫反应。 Agnolon 等人发现，MF59 与 MPLA 和明矾的组合相似，均能增加 IgG2a 抗体滴度，刺激 Th1 反应，并通过血清抗体阻断 FHA 与人类肺上皮细胞的结合。与 MPLA 和明矾的组合相比，MF59 被证明是 TT 和 PRN 抗原最有效的佐剂。 MF59 已用于 65 岁以上人群的 Flaud® 流感疫苗，在诱导老年人强烈免疫反应方面显示出巨大潜力。对接受 Focetria®（MF59 佐剂 A/H1N1 大流行性流感疫苗）的孕妇的研究表明，MF59 佐剂 A/H1N1 大流行性流感疫苗在怀孕期间是安全的。这表明 MF59 也可能在成人百日咳疫苗的加强接种中发挥作用。 表 2：aP 疫苗中新型佐剂的临床前研究 五、aP 疫苗的黏膜佐剂 百日咳影响上呼吸道，因此呼吸道黏膜免疫在预防百日咳感染中至关重要。人类百日咳感染会在鼻腔分泌物中产生 IgA，尽管没有证据表明 IgA 缺乏与百日咳感染有关，但恢复期患者鼻腔洗液中的抗百日咳分泌型 IgA（sIgA）和血清 IgA 已被证明能抑制百日咳杆菌对人类呼吸道上皮细胞的黏附。 除了 IgA，组织驻留记忆 T（TRM）细胞在黏膜免疫中也起着关键作用。在小鼠模型中，分泌 IL - 17 的 CD4 + TRM 细胞在初次感染时迁移至鼻组织，随后介导 Siglec - F + 中性粒细胞的募集。此外，再次感染时 IL - 17 - CD4 + TRM 细胞在局部扩增，有助于从鼻腔清除百日咳杆菌（图 2）。肌肉注射含铝佐剂的 aP 疫苗可诱导 Th2 免疫，但不会促进呼吸道中的 sIgA 或 TRM 细胞。因此，黏膜免疫可能在预防鼻腔定植和感染方面更有效。开发新型佐剂的目的是促进鼻内免疫，以预防细菌在鼻腔定植和肺部感染。 霍乱毒素（CT）、大肠杆菌热不稳定肠毒素（LT）及其基因解毒突变体常用作黏膜佐剂。Ryan 等人将 aP 疫苗与无毒突变体 LKT63 或部分酶活性 LTR72 突变体联合用于鼻内免疫，发现两者都能增强抗原特异性血清 IgG 和分泌型 IgA，并加速肺部细菌清除。无毒突变体 LTK63 可增强 Th1 和 Th2 反应，而部分酶活性 LTR72 突变体更倾向于 Th2 反应。 尽管 LT 可以增强鼻内 aP 疫苗的免疫反应，但 CT 作为百日咳疫苗佐剂的免疫效果并不理想。Herland Berstad 等人发现，CT 与百日咳杆菌联合鼻内免疫未能增强 IgA 反应，反而显著降低了它，这可能是由于 CT 与鼻上皮相互作用，与百日咳杆菌制剂的成分竞争所致。Isaka 等人还发现，当重组霍乱毒素 B 亚单位（rCTB）与 DPT 疫苗联合用于鼻内免疫时，对百日咳类毒素（PTd）和福尔马林处理的丝状血凝素（fFHA）的黏膜佐剂作用不显著。 Orr 等人研究了百日咳杆菌的腺苷酸环化酶毒素（CyaA）作为黏膜佐剂经鼻内给予小鼠时的免疫效果。具有酶活性的 CyaA 和缺乏腺苷酸环化酶活性的 CyaA（CyaA*）与 Prn 共同给药可显著增强血清 IgG 反应。与 Prn 和 CyaA 相比，Prn 和 CyaA * 免疫导致肺部抗 Prn IgA 反应显著改善。然而，这两种佐剂都不如 LKT63 有效。 尽管 CT 和 LT 的佐剂活性已被广泛研究和认可，但它们可能导致贝尔氏麻痹，这限制了它们在人类疫苗中的使用。目前正在开发更安全有效的黏膜佐剂。Shi 等人将基于食品级乳酸乳球菌的新型细菌样颗粒（BLP）黏膜佐剂引入百日咳抗原（如 PT、FHA 和 PRN）中，进行腹腔和鼻内免疫，发现与明矾相比，鼻内免疫 BLPs 在鼻冲洗液中产生显著的抗 PT IgA 和抗 FHA IgA，在预防细菌定植和肺损伤方面更有效。 Boehm 等人配制了含 curdlan 佐剂（一种来自粪产碱菌的 1,3β 葡聚糖）的 DTaP 疫苗，curdlan 佐剂促进 DTaP 颗粒在上呼吸道的定位。与原始 DTaP 疫苗相比，curdlan 佐剂虽然没有增强对 FHA 和 PT 的抗体反应，但经鼻内免疫的含 curdlan 佐剂的疫苗在肺匀浆中诱导 IL - 17A 显著增加。无论腹腔还是鼻内给予含 curdlan 佐剂的疫苗，肺中都没有观察到 TRM 细胞的显著扩增。经鼻内给予的 DTaP 疫苗联合 curdlan 佐剂也能从呼吸道清除百日咳杆菌。 Galeas - Pena 等人开发了一种由 aP 抗原和 T - vant（一种来自细菌外膜囊泡的新型佐剂）组成的鼻内疫苗，该疫苗经鼻内给药时可促进 Th1 和 Th17 免疫反应，扩增 CD4 + T 细胞（可能是常规 TRM 细胞），并清除肺和鼻咽部的百日咳杆菌，此外，它还能诱导黏膜 IgA 和血清 IgG。 脂质体佐剂、STING 和 TLR 激动剂及其组合也可作为黏膜佐剂。Asokanathan 等人证明，当氢氧化铝与 CpG - ODN 联合使用时，百日咳疫苗可增加血清 PT、FHA 和 PRN 特异性 IgG 抗体。巨噬细胞或脾脏上清液中 NO 和 IFN - γ 的水平显著增加，表明免疫反应转向 Th1。 基于合成脂肽 LP1569 的研究，Allen 等人随后继续使用一种新的佐剂 LP - GMP，其中包含 LP1569 和 c - di - GMP。c - di - GMP 作为细胞内干扰素基因受体刺激因子（STING）。LP - GMP 能够激活小鼠和人类的 DCs，促进有效的 Th1 和 Th17 免疫。当与百日咳抗原共同免疫时，LP - GMP 可预防百日咳杆菌引起的鼻腔定植和肺部感染，并且在鼻内接种时比腹腔免疫诱导更多的呼吸道 TRM 细胞，其中很大一部分是分泌 IL - 17 的肺组织驻留 CD4 + 细胞。 Jiang 等人发现，鼻内给予激动剂 c - di - GMP 作为 aP 疫苗的佐剂可诱导 Th1 和 Th17 免疫，并显著增加肺中的 CD4 + TRM 细胞。含 c - di - GMP 佐剂的 aP 疫苗组比其他组（包括含氢氧化铝的 aP 疫苗）表现出更好的保护效果。此外，肺部炎症细胞浸润减少，呼吸道细菌负荷也减少。 Aibna 等人将 PRN、FHA 2/3 和百日咳毒素突变体与三重佐剂（包括 Toll 样受体（TLR）- 3 激动剂 poly（I:C）、宿主先天防御肽（IDR - 1002）、聚磷腈载体系统（PCEP）和阳离子 DDAB/DOPE 脂质体）联合用于鼻内免疫。这种疫苗可促进 Th1 型免疫，产生高 IgG2a 和 IgA 血清抗体滴度，单次给药后产生鼻腔分泌的 sIgA 抗体。六、百日咳联合疫苗的稳定性 如上所述，百日咳联合疫苗通常包括白喉、破伤风类毒素、百日咳杆菌纯化亚单位蛋白、灭活脊髓灰质炎病毒抗原等。这种联合疫苗通常需要多次注射，且制成液体制剂，这对疫苗在长期储存过程中的稳定性提出了很高的要求。 联合疫苗的稳定性相当复杂，取决于各组分之间的相互作用。当疫苗中含有佐剂时，百日咳抗原、白喉类毒素和乙肝抗原会竞争佐剂上的结合位点，导致其他抗原经常取代白喉类毒素，从而降低白喉类毒素的效力。 Kalbfleisch 等人研究表明，近 90% 的单价抗原 DT、TT 和 FHA 可吸附在磷酸铝上，而 PRN、PT 和 FIM 的吸附率较低。与磷酸铝吸附后，DT 和 TT 比其他抗原表现出更明显的结构变化。Duprez 等人对含基因修饰百日咳毒素（gdPT）和 TLR 激动剂（E6020 和 CpG）且吸附于 AlOOH 佐剂的无细胞百日咳疫苗 Tdap 进行了表征，与 Tdap-AlOOH 和 Tdap-E6020（TLR4 激动剂）-AlOOH 相比，Tdap-CPG-AlOOH 表现出更好的热稳定性，且 FTIR 分析表明，与 PT 相比，gdPT 被 AlOOH 吸附后其二级结构基本保持不变。 抗原在铝佐剂上的解吸动力学会影响储存稳定性。以 Al (OH)₃为基础的 Infanrix 疫苗在 4°C 下储存长达 3 年时，所有批次的 PT、FHA 和 PRN 解吸率分别低于 3%、0.8% 和 0.1%。当抗原吸附在 AlPO₄上时，18-24 个月后 PT 的最大损失为 11-12%，而 PRN 在 2 年后逐渐解吸至 60% 的水平。吸附在磷酸铝上可能导致对小鼠鼻内百日咳攻击的保护效果较差。 此外，防腐剂的存在和极端温度会影响百日咳联合疫苗的稳定性。白喉和破伤风类毒素在较高温度下往往相对稳定，而疫苗效力在冷冻条件下更易降低。高温和冷冻温度都会对百日咳疫苗产生影响，但冷冻的影响更为显著。百日咳成分在 22-25°C 下储存 2-8 周仍能保持 80% 的初始效力，而疫苗在 - 20°C 下保存 15 天，百日咳成分的效力会降低约 50%。 研究表明，疫苗的冷冻损伤与铝盐佐剂有关。铝盐佐剂的存在增加了疫苗对冷冻温度的敏感性。冷冻铝盐会破坏疫苗，且冷冻引起的铝佐剂表面羟基损伤会减少铝颗粒之间的排斥力，促进聚集体的形成，从而导致疫苗效力下降。Xue 等人发现，在 DTaP 和 DTwP 疫苗中添加丙二醇赋形剂可以保护疫苗免受冷冻损伤，且不影响疫苗的 pH 值、粒径分布和效力。 总体而言，在百日咳联合疫苗中，破伤风和白喉的成分比百日咳的成分更稳定，疫苗的整体稳定性受温度、赋形剂、佐剂等多种因素的影响。由于联合疫苗的复杂性，目前尚未得出明确的结论。七、结论与展望 本文全面概述了当前含百日咳抗原的联合疫苗，探讨了通过加入促进 Th1 和 Th17 反应的佐剂来增强 aP 疫苗免疫原性的方法，讨论了百日咳联合疫苗中一些有前景的佐剂（如 CpG-ODN、MPL 和 LPS）的实例，为 aP 疫苗制剂中新佐剂的选择提供了见解。此外，从肌肉注射转向鼻内接种百日咳疫苗可能进一步提高效力，本文总结了各种黏膜佐剂在百日咳疫苗中的应用，强调了它们增强免疫反应的潜力。 理想的佐剂应具有广泛的安全性，易于制造和施用，能有效激活体液和细胞免疫反应，并将不良反应降至最低。本文概述了各种在临床前动物试验中显示出保护作用的新型 aP 疫苗佐剂。其中，CpG、TLR7a、LP1569 和 MPL 在肌肉注射或腹腔注射时可防止百日咳杆菌在肺部或气管定植，而鼻内施用的黏膜佐剂如 LP-GMP 和 c-di-GMP 甚至可诱导鼻腔黏膜免疫并减少细菌负荷。在 Tdap 疫苗中对 MF59 与氢氧化铝 + MPLA 的比较表明，氢氧化铝 + MPLA 诱导的免疫反应起效更快。 此外，新型佐剂在百日咳疫苗中尚未直接进行比较。然而，先前的研究表明，大多数 TLR 激动剂可诱导抗原特异性 CD4 T 细胞，但只有更强的 TLR7/8 和 TLR3 激动剂可诱导 CD8 细胞毒性 T 细胞。除免疫效果外，佐剂生产的复杂性、稳定性以及诱导免疫耐受的可能性都需要进一步评估，以避免临床限制。在临床试验和市售疫苗中测试的 TLR 激动剂表现出稳定的化学性质和较低的生产成本，使其成为有前景的开发候选物。与传统的铝佐剂不同，TLR 激活剂不需要与抗原吸附，这似乎降低了开发复杂性。然而，对抗原 - 佐剂相互作用产生的稳定性和免疫原性的研究仍然至关重要。多种佐剂的联合使用为未来 aP 疫苗的开发提供了另一条有前景的途径。我们认为，在百日咳疫苗中使用 TLR 激动剂，特别是已证明安全的 CpG 和 AS04，将成为一种普遍趋势。值得注意的是，虽然新型佐剂有助于诱导免疫增强和长期保护，但尚不清楚它是否能克服抗原缺陷菌株的选择压力，这方面还需要更多的研究。 传统上，新型佐剂的发现和选择依赖于对候选化合物的经验性筛选和优化，对其免疫机制的理解有限。此外，必须仔细考虑新型佐剂与其他疫苗成分的相互作用。这些传统方法通常成本高昂、耗时，并且在对佐剂机制和毒性缺乏清晰了解的情况下，难以符合疫苗安全性和有效性标准。因此，开发含新型佐剂的 aP 联合疫苗仍然是一个复杂而漫长的过程。 人工智能（AI）的最新进展为佐剂的发现和选择开辟了新途径。AI 利用虚拟评估，根据候选化合物的化学结构评估其生物活性，并预测它们与特定靶点的相互作用，从而能够快速识别活性佐剂。此外，AI 可以通过定量结构 - 活性关系（QSAR）模型研究佐剂的理化性质与生物活性之间的关系，促进佐剂制剂的合理优化。尽管 AI 技术尚未广泛应用于 aP 疫苗新型佐剂的开发，但其改变这一领域的潜力是不可否认的。AI 的整合必将推动 aP 疫苗设计和优化的重大进展。 此外，必须努力提高发展中国家的百日咳疫苗覆盖率，降低婴儿死亡率。在资源有限的偏远地区维持百日咳疫苗的稳定性需要对冷链基础设施进行大量投资。通过赋形剂、佐剂和制剂技术的进步来提高疫苗稳定性，有助于确保资源受限的发展中国家更好地获得有效的疫苗。 理想的百日咳疫苗应具有优异的安全性和稳定性，能引发体液和细胞免疫，提供长期保护，且不干扰其他疫苗成分的效力。深入了解百日咳联合疫苗中佐剂的成分、机制和类型，可以加速改进型百日咳疫苗的开发和临床应用。通过应对这些挑战，我们可以更接近实现高效且全球可及的百日咳疫苗。 识别微信二维码，可添加药时空小编 请注明：姓名+研究方向！