Prophylactic Vaccines, Successes, Errors, and Complications

Abstract

In 2015, the most recent year for which US data are available, the vast majority of children between ages 19 and 36 months have received the full array of vaccines recommended to protect the health of the public.1Hill H.A. Elam-Evans L.D. Yankey D. et al.Vaccination Coverage Among Children Aged 19–35 Months—United States, 2015.MMWR Morb Mortal Wkly Rep. 2016; 65: 1065-1071Crossref PubMed Scopus (85) Google Scholar I was unable to locate comparable data for other countries. Although this is good news and represents a great public health success, the flip side of these figures represents the bad news. The data suggest that 6.3% of US children have not received the full complement of polio vaccine; 8.1% are still vulnerable to measles, mumps, and rubella; and 8.2% are not protected against chicken pox. I suppose it is possible that the unvaccinated cohort may contain some children with acquired immunity from exposure to infected persons. I was unable to locate an exact figure for the number of children in the United States who are aged 2 years. However, I found a figure of 23.7 million children younger than age 6 years in 2015.2ChildStats.gov. Forum on child and family statistics. www.childstats.gov/americaschildren/tables/pop1.asp. Accessed June 8, 2017.Google Scholar Assuming that there are relatively equal numbers of children at each of the 6 age levels, this means that there are approximately 4 million children in the United States who are aged 2 years. Using a conservative figure of 8%, this means that there are a minimum of ~320,000 unimmunized 2-year-old children, a group that could be protected fully. The report also noted that poor children, compared with those whose families are above the so-called poverty level, were less likely to be vaccinated. For example, vaccination against rotavirus, a common childhood pathogen, is estimated at 68% versus 76.8% in children living below versus above the poverty level, respectively; full coverage against diphtheria, tetanus, and pertussis is 80.2% versus 87.1%, respectively.1Hill H.A. Elam-Evans L.D. Yankey D. et al.Vaccination Coverage Among Children Aged 19–35 Months—United States, 2015.MMWR Morb Mortal Wkly Rep. 2016; 65: 1065-1071Crossref PubMed Scopus (85) Google Scholar If children do not receive recommended immunizations by age 3 years, it seems to me they are not likely to be vaccinated by age 6 years. This suggests a guesstimate of at least 1 million vulnerable preschool-aged children. Also at risk are immunocompromised children who are prohibited from receiving vaccines. In a previous Editor-in-Chief’s Note, I discussed the relatively low use in pre- and early adolescent children of the vaccines against human papillomavirus (HPV).3Shader R.I. Human papillomavirus infections, more on colchicine, and some farewells and welcomes.Clin Ther. 2014; 36: 2-3Abstract Full Text Full Text PDF Scopus (2) Google Scholar Fortunately, this situation is improving. In a March 2017 report, the Centers for Disease Control and Prevention (CDC) estimated that 60% of teenaged girls and 50% of teenaged boys are now vaccinated against HPV.4Centers for Disease Control and Prevention. HPV vaccination coverage data. March 10, 2017. www.cdc.gov/hpv/hcp/vacc-coverage.html, Accessed June 8, 2017.Google Scholar The CDC contrasts these rates with the roughly 80% of boys and girls who have received vaccinations for diphtheria, tetanus, pertussis, and meningococcal meningitis. In this report, the CDC also suggests that it is a missed opportunity when these vaccines are not all given at the same time. I understand the practicality of this advice, yet it seems that we have no data about giving HPV vaccinations to preschool-aged children; this advice may be premature. Not all vaccines are consistently effective. In the United States, this has been particularly notable for the influenza vaccine.5Shader RI. Influenza vaccines-thoughts and current status. Clin Ther. 203;35:101-2.Google Scholar Typically, 3 strains are chosen for each year’s vaccine. Either because of incorrect choices or the mutability of these viruses, in some years the vaccine may only protect from 60% to 70% of the population. It is not yet clear whether 4-strain vaccines will be more effective year to year. A recent study of 9003 elderly, vaccinated persons from the 2014–2015 epidemic found that a quadrivalent, recombinant vaccine was 30% more effective than a quadrivalent, egg-grown, inactivated vaccine.6Dunkle L.M. Izikson R. Patriarca P. et al.Efficacy of recombinant influenza vaccine in adults 50 years of age and older.N Engl J Med. 2017; 376: 2427-2436Crossref PubMed Scopus (156) Google Scholar The attack rate was 2.2% versus 3.1%. Whereas the former was statistically better than the latter, both vaccines appear to have been protective. The existence of many strains has also plagued the development of a consistently effective vaccine for HIV.7HIV.gov. HIV vaccines. https://www.hiv.gov/hiv-basics/hiv-prevention/potential-future-options/hiv-vaccines. Accessed June 8, 2017.Google Scholar The search for a preventive vaccine has now gone on for about 30 years. In addition to the problem of multiple variants of the virus, the lack of a workable animal model in which a vaccine can be tested also complicates the search. The need for animal models is important in vaccine development. The Animal Efficacy Rule was authorized by the US Congress and the Food and Drug Administration (FDA) in 2002. This rule (CFR 314.600-650) allows the FDA to make greater use of animal efficacy data for the approval of drugs or vaccines for serious, life-threatening diseases or conditions stemming from exposure to toxic substances. In 2014, the FDA issued a draft update called Product Development Under the Animal Rule.8Food and Drug Administration. Product Development Under the Animal Rule Guidance for Industry. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM399217.pdf. Accessed June 8, 2017.Google Scholar This version stresses the importance of studying the translation of animal studies to human use, pointing out that humans and animals may be vulnerable to different virulent strains and that immune markers may not be the same. These emphases are particularly relevant for vaccine development. The 21st Century Cures Act of 2016 further eases what is needed for drug or vaccine approval by allowing sponsors to use data from observational studies, insurance claims, patient input, and other anecdotal data.9The 21st Century Cures Act. https://en.wikipedia.org/wiki/21st_Century_Cures_Act. Accessed June 8, 2017.Google Scholar Whether these legislated alterations in what is needed to bring new agents to market will improve the efficacy and safety of vaccines or the speed of bringing them to the public remains to be established. Not all complications attributed to vaccines are toxicity issues. The Vaccine Adverse Event Reporting System in the United States tracks and reports immunization discrepancies.10VAERS. Vaccine Adverse Event Reporting System. www.vaers.hhs.gov. Accessed June 8, 2017.Google Scholar The Vaccine Adverse Event Reporting System database for the 14 years between the beginning of 2000 and the end of 2013 contained 20,585 reports of 21,843 errors.11Hibbs B.F. Moro P.L. Lewis P. et al.Vaccination errors reported to the Vaccine Adverse Event Reporting System, (VAERS) United States, 2000-2013.Vaccine. 2015; 33: 3171-3178Crossref PubMed Scopus (44) Google Scholar One-quarter of those reported errors were associated with adverse events. Fortunately, 92% were considered to be nonserious. What alarms me about their findings is that the incorrect vaccine was sometimes administered (15% of reports), usually because of vaccine name confusion (eg, varicella vs zoster), and there were also problems with storage and the use of expired vaccines. In an onsite inspection study in 2010 by the Office of the Inspector General of the Department of Health and Human Services, vaccines for children were subjected to improper temperatures for at least 5 cumulative hours during a 2-week monitoring period in about three-quarters (n = 34) of the 45 sites selected for inspection.12Department of Health and Human Services. Office of the inspector general. Vaccines for children program: vulnerabilities in vaccine management. Daniel R. Levinson, Inspector General. June 2012. OEI-04-10-0043. https://oig.hhs.gov/oei/reports/oei-04-10-00430.pdf. Accessed June 8, 2017.Google Scholar Incorrect temperatures can alter the safety and efficacy of vaccines. Questions are sometimes raised about the safety of additives to vaccines. Thimerosal is a mercury-containing preservative added to some vaccines, although its use has declined. Although there have been charges that thimerosal-containing vaccines can be a source for mercury poisoning and a cause of neurodevelopmental disorders and autism, the FDA has unequivocally refuted these claims.13Food and Drug Administration. Thimerosal and vaccines. https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/UCM096228. Accessed June 8, 2017.Google Scholar More recently, aluminum has been identified as a cause of vaccine-related macrophagic myofasciitis (MMF).14Cherin P. Authier F.-J. Creange A. et al.Central nervous system disease in patients with macrophagic myofasciitis.Brain. 2001; 124: 974-983Crossref PubMed Scopus (117) Google Scholar, 15Gherardi R.K. Coquet M. Chérin P. et al.Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle.Brain. 2001; 124: 1821-1831Crossref PubMed Scopus (292) Google Scholar MMF presents as muscle weakness, tenderness, and pain and joint pain at or near the site of a vaccine injection and with fever and fatigue. Muscle biopsy reveals aluminic granulomas caused by embedded aluminum.15Gherardi R.K. Coquet M. Chérin P. et al.Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle.Brain. 2001; 124: 1821-1831Crossref PubMed Scopus (292) Google Scholar MMF cases have mostly been reported in France where the tissue pathology studies were conducted. Aluminum is sometimes added to vaccines as an adjuvant to enhance immune responses. As a result of the French cases, the film Injecting Aluminium16Injecting Aluminum. https://www.facebook.com/injectingaluminum. Accessed June 8, 2017.Google Scholar was released that asserts that aluminum is a neurotoxin. According to the film, premarketing animal toxicology was conducted on only 2 rabbits, and any muscle tissue samples from the study are no longer available. Injecting Aluminum was made by the French docujournalist Marie-Ange Poyet; it is available from Cinema Libre Studio. In the United States, the FDA posits that any risk from aluminum adjuvants is extremely low and that its benefits outweigh any risks.17Food and Drug Administration. Study reports aluminum in vaccines poses extremely low risk to infants. https://www.fda.gov/biologicsbloodvaccines/scienceresearch/ucm284520.htm. Accessed June 8, 2017.Google Scholar The total body burden during a child’s first year of life from both vaccines and diet is said to be less than the minimum risk levels promulgated by the Agency for Toxic Substances and Disease Registry.18Keith L.S. Jones D.E. Chou C.H. Aluminum toxicokinetics regarding infant diet and vaccinations.Vaccine. 2002; 20: 513-517Crossref Scopus (60) Google Scholar, 19Mitkus R.J. King D.B. Hess M.A. et al.Updated aluminum pharmacokinetics following infant exposures through diet and vaccination.Vaccine. 2011; 29: 9538-9543Crossref PubMed Scopus (82) Google Scholar Other assorted issues with vaccinations are sporadic outbreaks of diseases such as measles that are spread from and to unvaccinated children,20Centers for Disease Control and Prevention. Measles cases and outbreaks. https://www.cdc.gov/measles/cases-outbreaks.html. Accessed June 8, 2017.Google Scholar shortages of needed vaccines (eg, during a yellow fever crisis in 2016 in Angola and the Democratic Republic of the Congo, a United Nations/World Health Organization shipment of more than 1 million doses disappeared21Cheng M, Larson K. Amid worst yellow fever outbreak in decades, 1 million vaccines go missing. http://www.latimes.com/world/la-fg-yellow-fever-vaccines-disppear-20160804-snap-story.html. Accessed June 8, 2017.Google Scholar and the CDC has announced that, due to manufacturing problems, the US supply of yellow fever vaccine is inadequate),22Gershman M.D. Angelo K.M. Ritchey J. et al.Addressing a yellow fever vaccine shortage—United States, 2016–2017.MMWR Morb Mortal Wkly Rep. 2017; 66: 457-459Crossref PubMed Scopus (33) Google Scholar and the need for effective and adequate supplies of vaccines for the Ebola and Zika viruses. This month our Specialty Update focuses on vaccines.23Jhaveri R. Vaccines.Clin Ther. 2017; 39: 1516-1518Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 24McClure C.C. Cataldi J.R. O'Leary S.T. Vaccine hesitancy.Clin Ther. 2017; 39: 1550-1562Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 25Chong P.P. Avery R.K. A comprehensive review of immunization practices in solid organ transplant and hematopoietic stem cell transplant recipients.Clin Ther. 2017; 39: 1581-1598Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 26Cortes-Penfield N.W. Ramani S. Estes M.K. Atmar R.L. Prospects and challenges in the development of a norovirus vaccine.Clin Ther. 2017; 39: 1537-1549Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 27Collins M. Metz S.W. Progress and works-in-progress: Update on flavivirus vaccine development.Clin Ther. 2017; 39: 1519-1536Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 28Drozd E. Miller L. Johnsrud M. Impact of pharmacist immunization authority on seasonal influenza immunization rates across states.Clin Ther. 2017; 39: 1563-1580Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar It has been assembled by Topic Editor for Infectious Diseases Dr Ravi Jhaveri. This month’s Infectious Diseases Vaccines Update is a special feature which is available as FREE ACCESS content on the journal’s website. A previous Vaccines Update entitled “Youth and Children Vaccines Update” was published in Volume 35, Number 2 of Clinical Therapeutics. To view the previous Vaccines Update, see the articles below:1.Walson PD. Vaccines Update in Clinical Therapeutics.2.Caplan AL. Morality of Influenza Vaccine Mandates. Clin Ther 2013;35(2):106-108.3.Shann F. Nonspecific Effects of Vaccines and the Reduction of Mortality in Children.4.Wiedermann BL. What's Wrong With Acellular Pertussis Vaccines?5.Klok RM, Lindkvist R-M, Ekelund M, et al. Cost-Effectiveness of a 10- Versus 13-Valent Pneumococcal Conjugate Vaccine in Denmark and Sweden.6.Walson PD, Halvorsen M, Edge J, et al. Pharmacokinetic Comparison of Acetaminophen Elixir Versus Suppositories in Vaccinated Infants (Aged 3 to 36 Months): A Single-Dose, Open-Label, Randomized, Parallel-Group Design.Readers are also referred to the HPV Vaccine Update entitled “Helping Physicians Vaccinate: Making a Case for the HPV Vaccine,” published in Volume 36, Number 1 of Clinical Therapeutics. To view the HPV Vaccine Update, see the articles below:1.Duska LR. Safety and Success of the Human Papillomavirus Vaccine: Time for a Robust Vaccination Program in the United States and Worldwide.2.Erickson BK, Landers EE, Huh WK. Update on Vaccination Clinical Trials for HPV-Related Disease.3.Garland SM. The Australian Experience With the Human Papillomavirus Vaccine.4.Jeudin P, Liveright E, del Carmen MG, Perkins RB. Race, Ethnicity, and Income Factors Impacting Human Papillomavirus Vaccination Rates.5.Lazenby GB, Taylor PT, Badman BS, et al. An Association Between Trichomonas vaginalis and High-Risk Human Papillomavirus in Rural Tanzanian Women Undergoing Cervical Cancer Screening. This month’s Infectious Diseases Vaccines Update is a special feature which is available as FREE ACCESS content on the journal’s website. A previous Vaccines Update entitled “Youth and Children Vaccines Update” was published in Volume 35, Number 2 of Clinical Therapeutics. To view the previous Vaccines Update, see the articles below:1.Walson PD. Vaccines Update in Clinical Therapeutics.2.Caplan AL. Morality of Influenza Vaccine Mandates. Clin Ther 2013;35(2):106-108.3.Shann F. Nonspecific Effects of Vaccines and the Reduction of Mortality in Children.4.Wiedermann BL. What's Wrong With Acellular Pertussis Vaccines?5.Klok RM, Lindkvist R-M, Ekelund M, et al. Cost-Effectiveness of a 10- Versus 13-Valent Pneumococcal Conjugate Vaccine in Denmark and Sweden.6.Walson PD, Halvorsen M, Edge J, et al. Pharmacokinetic Comparison of Acetaminophen Elixir Versus Suppositories in Vaccinated Infants (Aged 3 to 36 Months): A Single-Dose, Open-Label, Randomized, Parallel-Group Design. Readers are also referred to the HPV Vaccine Update entitled “Helping Physicians Vaccinate: Making a Case for the HPV Vaccine,” published in Volume 36, Number 1 of Clinical Therapeutics. To view the HPV Vaccine Update, see the articles below:1.Duska LR. Safety and Success of the Human Papillomavirus Vaccine: Time for a Robust Vaccination Program in the United States and Worldwide.2.Erickson BK, Landers EE, Huh WK. Update on Vaccination Clinical Trials for HPV-Related Disease.3.Garland SM. The Australian Experience With the Human Papillomavirus Vaccine.4.Jeudin P, Liveright E, del Carmen MG, Perkins RB. Race, Ethnicity, and Income Factors Impacting Human Papillomavirus Vaccination Rates.5.Lazenby GB, Taylor PT, Badman BS, et al. An Association Between Trichomonas vaginalis and High-Risk Human Papillomavirus in Rural Tanzanian Women Undergoing Cervical Cancer Screening.