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PubMed2003

Development and clinical testing of multivalent vaccines based on a diphtheria-tetanus-acellular pertussis vaccine: difficulties encountered and lessons learned.

The widespread use of whole-cell pertussis vaccines in the second half of the 20th century have reduced the incidence of the disease significantly. However, in some countries, concerns about the reactogenicity and potential neurological damage associated with whole-cell vaccines led to a decrease in vaccine acceptance and an increase in morbidity and mortality of pertussis in several countries. This prompted the development of less reactogenic acellular pertussis vaccines combined with diphtheria and tetanus toxoids, initially in Japan and later in other countries. In Europe, the improved diphtheria, tetanus and acellular pertussis (DTPa) vaccine was first introduced in March 1994. The pertussis component of this DTPa vaccine, developed by Glaxo SmithKline, consists of pertussis toxoid, filamentous haemagglutinin and pertactin. The vaccine is well tolerated, with a lower incidence of adverse reactions than after administration of whole-cell vaccines. The long-lasting efficacy and effectiveness of DTPa vaccines have been extensively documented and these are now the cornerstone of a large range of combined vaccines including DTPa-hepatitis B (HBV), DTPa-inactivated polio (IPV) and DTPa-HBV-IPV. A lyophilised Haemophilus influenzae type b (Hib) vaccine can be reconstituted with all of these liquid combinations. The introduction of well-tolerated and efficacious DTPa vaccines and their more polyvalent combinations has improved the acceptance and simplified the implementation of childhood immunisation. This paper is a review of the technical and scientific difficulties encountered and the lessons learned over the 10-year period that it took to develop and introduce six multivalent vaccines using the Glaxo SmithKline DTPa as a building block.

Clinical Trials as Topic↗

PubMed1996

Booster vaccination against diphtheria and tetanus in man. Comparison of three different vaccine formulations--III.

Adverse reactions and antibody levels were compared following a booster vaccination of 177 Danish military recruits with a plain, an aluminium hydroxide (0.5 mg Al per human dose, HD) and a calcium phosphate (0.25 mg Ca per HD) adsorbed diphtheria-tetanus (D-T) vaccine. The calcium phosphate adsorbed vaccine was given in a HD of 3 Lf of D and T toxoids and proved to be of equal efficacy as the aluminium hydroxide adsorbed vaccine which was injected in a dose containing twice the antigen amount. The calcium phosphate vaccine caused fewer adverse reactions than the one adsorbed to aluminium hydroxide. The plain vaccine (6 Lf per HD of D and T toxoid) had the highest efficacy with a similar low occurrence of adverse reactions as the calcium phosphate adsorbed vaccine. Potency assays in mice were in accordance with these immunogenicity results in man if a two dose immunization schedule was followed, but not if the vaccines were compared after a single immunization as requested by the procedure for potency testing according to current WHO and European Pharmacopoeia requirements. Both of the adsorbed vaccines primed mice for specific IgE antibody formation. This could be detected after a second immunization with either of the adsorbed vaccines or with the plain D-T vaccine. Also in humans, immunization with the plain vaccine boosted specific IgE formation to a detectable level. This may be ascribed to adjuvant priming during the primary vaccination series some 20 years previously.

Adolescent↗

PubMed1999

The effect of smoking on influenza, influenza vaccination efficacy and on the antibody response to influenza vaccination.

We examined the relation between cigarette smoking and (1) the occurrence of influenza, (2) the efficacy of influenza vaccination and (3) the antibody response to influenza vaccination in fifteen family practices in South-Limburg, the Netherlands, during the influenza season 1991 1992. Data were used from a randomized double-blind placebo-controlled trial into the efficacy of influenza vaccination in which smoking status was measured 10 weeks after the start of the trial. A total of 1838 subjects aged 60 years or older, of whom 1531 subjects (321 smokers, 1152 non-smokers and 58 cigar/pipe smokers) who returned the smoking questionnaire and were not previously vaccinated, were used in the analyses. The main outcome measures were serological influenza (fourfold increase of antibody titre between 3 weeks and 5 months after vaccination); clinical influenza as determined by criteria of the Dutch Sentinel Stations from self reported symptoms in postal questionnaires 10 weeks and 5 months after vaccination; increases after vaccination and decreases after 5 months in logarithmic titres of antibody against the vaccine strains. No relation between smoking and either serological or clinical influenza was found, although the risk for serological influenza was slightly (not significantly) elevated in smokers compared to non-smokers. A statistical interaction was found between smoking and vaccination when serological influenza was the outcome measure indicating that the efficacy of vaccination was greater in smokers than in non-smokers (comparison of model with and without interaction; likelihood ratio test, p < 0.0001). This finding is supported by a greater titre rise 3 weeks after vaccination for two out of four strains, but not by the antibody response after vaccination in previous studies on influenza and other infectious diseases. Also, this possible difference of immunogenicity is not reflected in a better protection for clinical influenza. The rise in antibody titre 3 weeks after vaccination was higher in smokers for A/Singapore/6/86 and B/Beijing/11/87, but not for the other two strains. Decline in titres after 5 months was similar for smokers and non-smokers. We conclude that smoking has no clinical or preventive significance for risk of influenza in the elderly.

Aged↗

PubMed1999

Humoral responses in mice following vaccination with DNA encoding glutathione S-transferase of Fasciola hepatica: effects of mode of vaccination and the cellular compartment of antigen expression.

The humoral responses in mice following vaccination with DNA constructs encoding Fasciola hepatica glutathione S-transferase (GST) have been evaluated. GST47 cDNA was subcloned into two DNA vaccine vectors, VR1012 and VR1020, which direct expression to the cytoplasmic and extracellular compartments, respectively. Expression was confirmed by transfection into COS 7 cells. Groups of mice were vaccinated with these constructs, by either intramuscular injection with the VR1012-or VR1020-based constructs, or intradermal vaccination (with a gene gun) with the VR1020-based construct. Vaccination with the construct designed for secretion resulted in an increased humoral response compared to vaccination with the nonsecretory construct. The level of the total humoral response after vaccination with the secretion construct was not dependent on the route of vaccination. However, the isotype profile of the response differed between the groups; intramuscular vaccination with the construct directing cytoplasmic expression yielded an immuoglobulin (Ig)G2a dominant (Th1-type) response, intradermal vaccination with the secretory construct a IgG1/IgE dominant (Th2-type) response, and intramuscular vaccination with the secretory construct a mixed isotype response. These results demonstrate that the immunogenicity of a DNA vaccine based on Fasciola GST, as well as the isotype of the response against GST, is determined by the mode of vaccine administration.

Animals↗

PubMed2003

Studies on the safety and immunogenicity of the South African bluetongue virus serotype 2 monovalent vaccine: specific detection of the vaccine strain genome by RT-PCR.

In order to study the safety and the immunogenicity of the South African vaccine against the serotype 2 bluetongue virus, two groups of seven sheep were vaccinated with the vaccine used in the French island of Corsica. Vaccinated and non-vaccinated sheep were observed clinically and their rectal temperatures were recorded daily. The serological response in vaccinated animals confirmed the immunogenicity of the vaccine. Post-vaccinal viraemia was investigated and the vaccine genome was detected by reverse transcription polymerase chain reaction (RT-PCR). No viraemia was observed at post-vaccination days 4, 7 and 11 but the vaccine strain of virus was detected by RT-PCR throughout the experiment. The thermostability of the vaccine was also evaluated. The vaccine titre strongly decreased at temperatures higher than 35 degrees C.

Animals↗

PubMed2004

Postmarketing safety surveillance for typhoid fever vaccines from the Vaccine Adverse Event Reporting System, July 1990 through June 2002.

Vaccines against Salmonella enterica serotype Typhi are used for prophylaxis of international travelers and have potential use as counterbioterrorism agents. The Vaccine Adverse Event Reporting System (VAERS) cannot usually establish causal relationships between vaccines and reported adverse events without further research but has successfully detected unrecognized side effects of vaccine. We reviewed reports to VAERS for US-licensed typhoid fever vaccines for the period of July 1990 through June 2002. We received 321 reports for parenteral Vi capsular polysaccharide vaccine and 345 reports for live, oral, attenuated Ty21a vaccine, with 7.5% and 5.5%, respectively, describing death, hospitalization, permanent disability, or life-threatening illness. Unexpected frequently reported symptoms included dizziness and pruritus for Vi vaccine and fatigue and myalgia for Ty21a vaccine. Gastroenteritis-like illness after receipt of Ty21a vaccine and abdominal pain after receipt of Vi vaccine, which are previously recognized events, occasionally required hospitalization. Nonfatal anaphylaxis was reported after both vaccines. VAERS reports do not indicate any unexpected serious side effects that compromise these vaccines' use for travelers' prophylaxis.

Adverse Drug Reaction Reporting Systems↗

PubMed1973

Immune response in primates vaccinated with duck embryo cell culture rabies vaccine.

Adult rhesus monkeys (Macaca mulata) were vaccinated with four inactivated rabies vaccines, including two cell culture vaccines, one zonal purified cell culture vaccine, and a 10% extracted duck embryo vaccine. The vaccines were potency tested by both National Institutes of Health (NIH) and Habel methods and passed one or both tests. However, a vaccine having acceptable potency by one method frequently failed or was marginal by the other procedure. Groups of three monkeys were inoculated with each vaccine by one of two schedules. The first consisted of four weekly 1-ml doses followed by a 1-ml booster dose at 6 months, and the second consisted of seven daily 1-ml doses of vaccine with no booster. Both zonal purified and extracted duck embryo vaccines induced detectable neutralizing antibody by day 7 with either schedule, and antibody titers elicited by the cell culture vaccine remained high through 210 days. However, antibody titers produced by the 10% duck embryo vaccine dropped sharply after their 28-day peak. Duck embryo cell culture vaccines with low or marginal potency as measured by Habel or NIH tests still produced rapid, high levels of serum-neutralizing antibody in primates. LD(50) or NIH and Habel tests as measured in mice were not necessarily good indices of antibody response in the primate host. The need for a cell culture potency test that will yield a more predictable correlation with the definitive host's antibody response is discussed.

Adjuvants, Immunologic↗

PubMedDate not supplied

[Influenza vaccination in healthcare workers. Why are some vaccinated whereas others are not].

BACKGROUND AND OBJECTIVE: Influenza vaccination is indicated in health professionals. Nevertheless, vaccination coverage in healthcare workers tends to be low. This paper determines the reasons why some workers are vaccinated whereas others are not and investigates what type of intervention can modify the latter attitude. METHOD: This was a cross-sectional descriptive study using a questionnaire survey. SETTING: workers at Hospital General Universitario de Alicante (Alicante, Spain). Absolute frequencies and relative frequencies expressed in percentages were calculated for each of the variables studied. Results were analyzed considering the professional categories of the persons involved and the departments where they worked. RESULTS: The reasons for influenza vaccination stated by hospital workers were to protect their health (65.6%), the belief that vaccination is beneficial (45.7%), and to avoid transmitting influenza to their patients (42.5%), and to their own families (39.8%). The main reasons for not undergoing vaccination were to avoid medication (17.9%), confidence in their own defenses (17%), or fear of the secondary effects of the vaccine (16.8%). CONCLUSION: The main reason given by hospital personnel for undergoing vaccination was to protect their own health and that of their family and patients. The reasons most frequently given for not undergoing vaccination were based on possible side effects of the vaccine, the conviction of not being part of a high-risk group, and doubts about the effectiveness of the vaccine as a protective agent. Many of the reasons given for not undergoing vaccination were based on erroneous beliefs and should be taken into account when designing strategies to increase influenza vaccination coverage among health personnel.

Attitude of Health Personnel↗

PubMed2006

Physician vaccinate thyself: why influenza vaccination rates are higher among clinicians than among nonclinicians.

BACKGROUND: National vaccination guidelines recommend influenza vaccination for clinical employees with patient contact. For many other healthy working adults, influenza vaccination is optional. PURPOSE: We examined acceptance of a free influenza vaccine among clinical university employees who had patient contact and nonclinical university employees who did not have patient contact. We asked whether and why job role had an influence on the decision to be vaccinated. METHOD: Clinical (n = 103) and nonclinical (n = 339) employees of two universities completed a mailed questionnaire. RESULTS: Vaccination rates were higher among clinical employees (62%) than among their nonclinical counterparts (47%). This effect of job role on vaccine acceptance was statistically mediated by perceived riskiness of getting vaccinated, knowledge about the vaccine, easy access to the vaccine, pro-Western medicine beliefs, and social influence. It was not vaccinated by perceived likelihood of getting infected or concern about infecting others. CONCLUSION: Clinical employees have higher vaccination rates than nonclinical employees, but not for the reasons that form the basis of national vaccination guidelines.

Adult↗

PubMed2004

Immunogenicity of three recombinant hepatitis B vaccines administered to students in three doses containing half the antigen amount routinely used for adult vaccination.

We evaluated the immunogenicity of three recombinant hepatitis B vaccines, one Brazilian (Butang, Instituto Butantan) and two Korean vaccines (Euvax-B, LG Chemical Ltd. and Hepavax-Gene, Greencross Vaccine Corp.), administered intramuscularly to students aged 17 to 19 years in three 10- micro g doses (corresponding to half the amount of antigen routinely used for adult vaccination) at intervals of one month between the first and second dose, and of four months between the second and third dose. A total of 316 students non-reactive for any serological marker of hepatitis B virus infection were vaccinated: 77 (24.4%) with the Butang vaccine, 71 (22.5%) with Euvax-B, 85 (26.9%) with Hepavax-Gene and, for comparison, 83 (26.2%) with Engerix-B (GlaxoSmithKline), whose efficacy in young adults at the dose used here has been confirmed in previous studies. Similar seroconversion rates (anti-HBs > 10 mIU/mL about one month after application of the third dose) were obtained for the Butang, Euvax-B, Hepavax-Gene and Engerix-B vaccines (96.2%, 98.6%, 96.5% and 97.6%, respectively). The frequency of good responders (anti-HBs > 100 mIU/mL) was also similar among students receiving the four vaccines (85.8%, 91.6%, 89.4% and 89.2%, respectively). The geometric mean titers (GMT) of anti-HBs about one month after the third dose obtained with these vaccines were 727.78 +/- 6.46 mIU/mL, 2009.09 +/- 7.16 mIU/mL, 1729.82 +/- 8.85 mIU/mL and 2070.14 +/- 11.69 mIU/mL, respectively. The GMT of anti-HBs induced by the Euvax-B and Engerix-B vaccines were higher than those obtained with the Butang vaccine (p < 0.05); this difference was not significant when comparing the other vaccines two-by-two. No spontaneous adverse effects attributable to the application of any dose of the four vaccines were reported.

Adolescent↗

PubMed2006

Evaluation of protection against virulent bovine viral diarrhea virus type 2 in calves that had maternal antibodies and were vaccinated with a modified-live vaccine.

OBJECTIVE: To evaluate the efficacy of an adjuvanted modified-live bovine viral diarrhea virus (BVDV) vaccine against challenge with a virulent type 2 BVDV strain in calves with or without maternal antibodies against the virus. DESIGN: Challenge study. ANIMALS: 23 crossbred dairy calves. PROCEDURES: Calves were fed colostrum containing antibodies against BVDV or colostrum without anti-BVDV antibodies within 6 hours of birth and again 8 to 12 hours after the first feeding. Calves were vaccinated with a commercial modified-live virus combination vaccine or a sham vaccine at approximately 5 weeks of age and challenged with virulent type 2 BVDV 3.5 months after vaccination. Clinical signs of BVDV infection, development of viremia, and variation in WBC counts were recorded for 14 days after challenge exposure. RESULTS: Calves that received colostrum free of anti-BVDV antibodies and were vaccinated with the sham vaccine developed severe disease (4 of the 7 calves died or were euthanatized). Calves that received colostrum free of anti-BVDV antibodies and were vaccinated and calves that received colostrum with anti-BVDV antibodies and were vaccinated developed only mild or no clinical signs of disease. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that the modified-live virus vaccine induced a strong protective immune response in young calves, even when plasma concentrations of maternal antibody were high. In addition, all vaccinated calves were protected against viral shedding, whereas control calves vaccinated with the sham vaccine shed virus for an extended period of time.

Animals↗

PubMed2000

[Studies on vaccination schedule of inactivated hepatitis A vaccine].

OBJECTIVE: To evaluate three vaccination schedules of inactivated hepatitis A vaccine in rhesus monkeys (Macaca Mulatta). METHODS: Seventeen rhesus monkeys were divided randomly into four groups. The first group of five monkeys was immunized with vaccination schedule 1 (one immunization at week 0); The second group of five monkeys was immunized with vaccination schedule 2 (first injection at week 0, and booster one at week 4); the third group of five monkeys was immunized with vaccination schedule 3 (first injection at week 0, and booster one at week 24); and the fourth group of two monkeys with MEM as control. Rhesus monkeys were inoculated by intramuscular injections to detect the ALT (alanine aminotransferase), liver pathology and anti-HAV at different time. RESULTS: During the 52-week observation, no abnormal elevation of ALT or liver pathology appeared. The IgG response for vaccination schedule 1 reached the highest level (13 219 mIU/ml), and decreased gradually to 2 056 mIU/ml at week 52. After booster immunization at week 4, the IgG response for vaccination schedule 2 was 13 863 mIU/ml at week 12, and decreased to 6 285 mIU/ml. The highest level of IgG (40 638 mIU/ml) for vaccination schedule 3 appeared at week 28 after booster injection at week 24. Further more, at week 52 the IgG level for vaccination schedule 3 was also the highest among the three vaccination schedules. CONCLUSIONS: The inactivated hepatitis A vaccine is safe and well immunogenic. The vaccination schedule 3 showed the best immune response among the three vaccination schedules.

Adult↗

PubMed1996

Technology to save millions, extends vaccine outreach programs. Vaccine management.

Program for Appropriate Technology in Health (PATH), Seattle, Washington, has collaborated in developing a technology that improves the delivery of vaccines in the developing world. HEATmarker is a vaccine vial label which changes color with exposure to heat over time. This allows health workers to verify--at time of use--that each vial of vaccine is in usable condition and has not lost its potency due to heat exposure. Vaccine vial monitors (VVMs) have recently been mandated on all oral polio vaccine purchased and distributed by UNICEF throughout the world. "Vaccine vial monitors will revolutionize the way vaccines are delivered, enabling them to be administered in remote areas, outside the reach of the traditional 'cold chain' that extends from manufacturer to consumer. As a result, millions more children in remote parts of the world will have access to oral polio and other vaccines," states Peter Evans of the World Health Organization (WHO), Global Programme for Vaccine and Immunization. Evans adds, "WHO expects that $10 million a year will be saved for oral polio vaccine alone." VVMs will enable health workers to use vaccine that would otherwise have been discarded. Until now, health workers disposed of any polio vaccine that may not have been properly refrigerated in transport or that had been opened but not used because they were unable to tell if it was potent. In the future, WHO intends to require VVMs on vaccines for measles, hepatitis B, and other childhood diseases, which will result in millions more lives and dollars being saved.

Americas↗

PubMed1963

THE VALUE OF DUCK-EMBRYO VACCINE AND HIGH-EGG-PASSAGE FLURY VACCINE IN EXPERIMENTAL RABIES INFECTION IN GUINEA-PIGS.

The authors have compared the value of multiple doses of duck-embryo and HEP Flury vaccine with that of pooled 5% sheep-brain vaccine in experimental rabies infection in guinea-pigs. They found that the duck-embryo vaccine given in a dosage corresponding to 14 ml of 10% vaccine (the dosage recommended for human treatment), either alone or with antirabies serum, gave no protection and that, even when administered in a dosage corresponding to 140 ml of 5% pooled vaccine, both the duck-embryo and the HEP Flury vaccines, whether alone or with serum, conferred little protection. Pooled phenolized vaccine under identical conditions gave good results. The immunogenicity of duck-embryo and HEP Flury vaccines, given before infection, was also inferior to that of pooled vaccine; and the duck-embryo vaccine was found to be a poorer antigen than the pooled vaccine in mouse potency tests.The authors conclude that the dosage of duck-embryo vaccine recommended for human treatment is inadequate and that the HEP Flury vaccine in its present form is unsuitable for post-infection treatment.

Animals↗

PubMed2003

Comparative study of the reactogenicity of a three-component acellular pertussis vaccine and whole-cell pertussis vaccine administered to healthy Singaporean infants.

The objective of this study was to assess and compare the reactogenicity of GlaxoSmithKline (GSK) Biologicals' diphtheria-tetanus-tricomponent acellular pertussis vaccine (DTPa) and the locally used combined diphtheria-tetanus-whole-cell pertussis vaccine (DTPw) as a primary vaccination course in healthy infants at the age of 3, 4 and 5 months. A phase IV, single-blinded, randomized comparative clinical study involved one hundred and eighty healthy infants with two study groups in a 2:1 ratio to receive either DTPa or DTPw vaccine which were administered intramuscularly at the right anterior-lateral aspect of the thigh. The incidence and intensity of local solicited symptoms such as pain, redness and swelling at injection site and general solicited symptoms such as fever and fussiness were evaluated. Serious adverse events were followed for one month after each vaccination. The overall incidence of local and general symptoms was significantly higher in the group receiving locally used DTPw vaccine as compared to the group receiving GSK DTPa vaccine. Solicited local symptoms, pain (47.4% vs 15.1%), redness (95.9% vs 84.9%) and swelling (46.2% vs 18.5%), were reported more frequently in the group receiving DTPw vaccine than in the group receiving DTPa vaccine. Fever (> or = 37.5 degrees C) (52% vs 14.6%) and fussiness (60.8% vs 33.6%) were also more commonly reported in the DTPw group. There were six serious adverse events reported (4 with DTPw and 2 with DTPa). None of them related to the study vaccines, as considered by the investigators. Thus it was found that GSK Biologicals' DTPa vaccine was significantly less reactogenic as compared to the locally used DTPw vaccine manufactured by Commonwealth Serum Laboratories when administered as a 3-dose primary vaccination course to healthy infants at the age of 3, 4 and 5 months in Singapore.

Diphtheria-Tetanus-Pertussis Vaccine↗

PubMed2006

Effect of recombinant canine distemper vaccine on antibody titers in previously vaccinated dogs.

Two canine distemper virus (CDV) vaccine types are currently commercially available: modified-live virus (MLV) vaccines and a canarypox recombinant CDV (rCDV) vaccine (Recombitek, Merial). This study compared the ability of the rCDV vaccine and MLV vaccines to significantly enhance (boost) the antibody response of previously immunized adult and juvenile dogs. A significant (fourfold or greater) increase in titer occurred in significantly more dogs revaccinated with Recombitek C-4 or Recombitek C-6 than with the MLV-CDV vaccines. This study demonstrates that Recombitek, the only vaccine for dogs containing rCDV, is more likely to significantly boost the CDV antibody response in previously vaccinated dogs than are the MLV-CDV vaccines. Because rCDV vaccine can boost the antibody titer of dogs previously vaccinated with an MLV vaccine, it can and should be used when core vaccines are readministered.

Animals↗

PubMed1990

[The effect of the emergent vaccination using DTP vaccine to control the outbreak of pertussis].

This paper reports the results of the effects of the emergent vaccination with DTP vaccine to control the outbreak of pertussis. Objects of observation were 4-6 years old children of kindergarten having pertussis vaccination and exposed history. The children were at random divided into two groups: 76 children were vaccinated with DTP vaccine and 72 children were inoculated with placebo. The results of observation: there was no strong and abnormal reaction in the vaccinated children; two weeks and three months after emergent vaccination with DTP vaccine, GMT antibody of pertussis were increased 18.14 and 4.73 times more than before vaccination respectively. There were no differences of the attack rates average days from vaccination to onset, average days of cough (P greater than 0.2) within 21 days after vaccination between the two groups. The protection rate was 62.11% three months after vaccination. The results showed that the emergent vaccination with DTP to control the outbreak of pertussis was safe and effective.

Child↗

PubMed1990

Mild measles and secondary vaccine failure during a sustained outbreak in a highly vaccinated population.

A prolonged school-based outbreak of measles provided an opportunity to study "vaccine-modified" mild measles and secondary vaccine failure. Thirty-six (97%) of 37 unvaccinated patients had rash illnesses that met the Centers for Disease Control clinical case definition of measles, but 29 (15%) of 198 vaccinated patients did not, primarily because of low-grade or absent fever. Of 122 patients with seroconfirmed measles, 10 patients (all previously vaccinated) had no detectable measles-specific IgM and significantly milder illness than either vaccinated or unvaccinated patients with IgM-positive serum. Of 108 vaccinated patients with seroconfirmed measles, 17 patients (16%) had IgM-negative serology or rash illnesses that failed to meet the clinical case definition; their mean age (13 years), age at the time of vaccination, and time since vaccination did not differ from those of other vaccinated patients. The occurrence of secondary vaccine failure and vaccine-modified measles does not appear to be a major impediment to measles control in the United States but may lead to underreporting of measles cases and result in overestimation of vaccine efficacy in highly vaccinated populations.

Adolescent↗