It is helpful to understand how vaccines are approved and then recommended as part of a schedule. The U.S. Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research (CBER) is responsible for regulating vaccines in the United States. Vaccine clinical development follows the same general pathway as drugs and other biologics. A sponsor who wishes to begin clinical trials with a vaccine must submit an investigational new drug application (IND) to the FDA. The IND describes the vaccine, its method of manufacture, and the types of quality control testing done prior to administering the vaccine to humans. Also included is information about the vaccine's safety and ability to elicit an immune response in animal testing. In addition, the IND contains the proposed clinical protocol.

The expansion of the recommended ages for the vaccination of children and adults against influenza is one of the most significant changes to the schedule in recent years. It requires an annual visit to a healthcare provider, including among older children and young adults who typically have low rates of physician visits.

The ACIP considered multiple factors in making this recommendation. First, according to accumulated evidence, the influenza vaccine appears to be both safe and effective, with the benefits of vaccination outweighing the small risk of adverse effects [21]. Widespread vaccination is also intended to lower the social and economic impact of influenza. The number of missed days of school for children and missed days of work for parents is substantial. Physician visits for the flu may lead to a prescription for antibiotics—treatment that is unnecessary and potentially dangerous.

The recommendation is also intended to simplify the decision to advise vaccination for children [21]. In previous years, vaccination was recommended for a number of groups with specific risk factors. These included older children with certain medical conditions and children who were close contacts of people who should be immunized. Making vaccination routine for all children is expected to lead to a 50% increase in coverage for those children who have a specific risk-based or contact-based indication.

Recommendation for Adolescents: HPV vaccine is recommended for girls and boys 11 to 12 years of age and for older adolescents who have not yet been vaccinated. Children 9 to 10 years of age may also be vaccinated.

Recommendation for Adults: HPV vaccine is recommended for adults up to 26 years of age who have not completed the vaccine series. HPV vaccine is also recommended for those 27 to 45 years of age if desired or if a risk factor is present.

Epidemiologic data on HPV incidence and age of sexual debut suggest that the pre-teen years are an appropriate time to begin HPV protection [32]. Genital HPV is the most common sexually transmitted infection in the United States, with 13 million new infections among people ≥15 years of age each year [95]. Teens and young adults are particularly at risk; about half of those infections occur in individuals 15 to 24 years of age [32]. One multisite, clinic-based study of sexually active females found the highest prevalence of HPV in girls 14 to 19 years of age. In another study, using a representative, population-based sample, HPV prevalence was 26.9% among sexually active women 18 to 25 years of age [33]. The prevalence of types 16 or 18 was 7.8%. Another study, also intended to be representative of the general population, found that the prevalence of HPV was 26.8% for women 14 to 59 years of age and nearly 45% among women 20 to 24 years of age [34]. In the overall study population, the prevalence of type 16 was 1.5%, and type 18 was 0.8%.

An important consideration in protecting adolescents who are not yet sexually active is that HPV infection is common within the first few years after sexual debut [32]. In addition, studies have shown high antibody titers with vaccination at age 11 to 12 years. The projected impact of vaccinating girls at 12 years of age is a 20% to 66% reduction in lifetime cervical cancer risk, depending on the effectiveness of the vaccine and the duration of protection. Vaccination could also lead to a 21% reduction in low-grade abnormalities on Pap tests over the life of a cohort of vaccinated females. A comparison of HPV prevalence data from the vaccine era (2009–2012) and the prevaccine era (2003–2006) found that the prevalence of the HPV types included in the quadrivalent vaccine decreased by 64% (from 11.5% to 4.3%) among girls 14 to 19 years of age [17]. Considering the modest uptake of this vaccine, the potential impact is significant.

The recommendation to vaccinate young adults takes into account the fact that many will already be sexually active and may have been exposed to one or more types of HPV. Young adults who are not yet sexually active can receive the full benefit of vaccination. In addition, it is likely that many individuals who are infected have not yet encountered each of the vaccine-covered types, so they can receive at least partial benefit [35,36]. The recommendation to vaccinate adults to the age of 26 years reflects the safety and efficacy testing on which the initial vaccines' approvals were based [30,31,37]. Use in older individuals is also effective, and many patients will benefit from vaccination at 27 to 45 years of age. Medical professionals can inform patients of the option to receive the vaccine series or to complete the series, help assess the benefits and individual risk factors, and facilitate decision-making. As noted, the HPV vaccine remains significantly underutilized as of 2024.

In 2009, the age parameters for vaccine administration were adjusted to harmonize the schedules of the two approved rotavirus vaccines [40]. One is a pentavalent reassortant vaccine based on a bovine rotavirus, often abbreviated as RV5. The other is a live, attenuated human rotavirus vaccine, often abbreviated as RV1. RV5 has a three-dose schedule, while RV1 requires two doses [41]. The maximum ages for these vaccines are somewhat different, according to their prescribing information, but an ACIP workgroup has concluded that safety and efficacy are unlikely to be affected if the same age limits are used for both [40].

Historically, before widespread vaccination, there were about 1,400 to 2,800 cases of meningococcal disease in the United States each year [42]. Although not a common illness, meningococcal disease has a rapid course and a high degree of mortality, with a case-fatality ratio of about 10% to 14%. Among survivors, 11% to 19% will experience serious sequelae, such as neurologic deficit, deafness, or loss of a limb [43]. The degree of severity means that, in addition to putting the patient's life at risk, each case requires a substantial public health effort to identify additional cases quickly and prevent the disease from spreading [44].

Recommendation for Adults: RZV is recommended for individuals 50 years of age and older with no vaccination history and for individuals who previously received the ZVL vaccine. RZV is also recommended for individuals 19 years of age or older who are immunocompromised or who will be immunodeficient/immunosuppressed due to disease or therapy.

There are an estimated 1 million cases of herpes zoster each year, and incidence increases with age [49]. Without vaccination, about one-third of Americans will experience shingles at some point in their lives [49]. In addition to discomfort and inconvenience for the patient, there is also a risk of viral transmission leading to primary varicella in at-risk contacts. Postherpetic neuralgia (PHN) is an unfortunate but fairly common complication. A community-based study in Minnesota looked at the incidence of PHN as defined by various durations of pain [50]. Eighteen percent of patients experienced PHN-type pain for at least 30 days, 13% for at least 60 days, and 10% for at least 90 days [50]. The ACIP added the zoster vaccine to the adult immunization schedule to take advantage of the opportunity to decrease both the burden of disease and the risk of complications. In 2018, the recombinant zoster vaccine (RZV) was added as the preferred vaccine, and in 2020, the ZVL vaccine was discontinued [19]. RZV has better proven efficacy in preventing herpes zoster compared with ZVL, and breakthrough cases are associated with less severe herpes zoster-related pain and less interference on activities of daily living [56].

The ACIP recommends that LAIV not be used in patients with asthma or other conditions predisposing to flu complications [12,21]. In most cases, IIV or another type can be used instead. LAIV should also be avoided in children and adolescents who are receiving aspirin or salicylate therapy. Acute respiratory illness with nasal congestion, which could interfere with delivery of the vaccine, is a reason to consider delaying the use of this vaccine until the congestion has decreased. Children younger than 5 years of age who have recent or recurrent wheezing should not receive LAIV [12,21].

Although measles was considered effectively eliminated in the United States in 2000, resurgence in the disease and regional outbreaks have resulted from suboptimal vaccination rates. In 2014, there were 667 cases of measles in the United States, more than 10 times the number of cases in 2000; another even larger spike occurred in 2019 (1,282 cases in 31 states) [6]. A large outbreak in 2014–2015 was linked to unvaccinated children visiting Disneyland, the source patient probably being infected overseas (likely the Philippines) [6]. The decrease in vaccine coverage is in part attributed to the false belief that the MMR vaccine may cause autism. Based on multiple studies, experts generally agree that there is no evidence for a link between the MMR vaccine and autism, and it is important that clinicians address these misconceptions with patients. In 2004, the Institute of Medicine (IOM) reported that "the body of epidemiological evidence favors rejection of a causal relationship between the MMR vaccine and autism" [83]. The American Academy of Pediatrics has also concluded that the evidence does not support such a connection. In addition, autism is not thought to be immune-mediated, and there is no clear mechanism by which MMR would cause this disorder [84].

Research on the topic includes a Canadian study involving 27,749 children born between 1987 and 1998 [85]. This study found no association between rates of pervasive developmental disorder and either one or two doses of the MMR vaccine. In a 2015 retrospective cohort study of 95,727 children, MMR vaccine receipt was not found to predict autism diagnosis, even among children with older siblings with an autism spectrum disorder [78]. A study of 657,461 children born in Denmark between 1999 and 2010 found no increased risk of autism in those who received the MMR vaccine, including in special subgroups (e.g., autism risk factors, other childhood vaccinations) [115].

Some of the concerns about autism involve the use of thimerosal, a mercury-containing preservative. The IOM has concluded that, as with concerns about MMR, the evidence favors rejecting the idea of a causal relationship between thimerosal-containing vaccines and autism [83]. In addition, the same study that looked at MMR and autism in a large cohort of Canadian children also looked for any relationship between ethylmercury exposure and autism and failed to find a connection [85]. Exposure levels were comparable to levels in the United States during the 1990s. Another study, which examined the incidence of autism in California children before and after thimerosal was removed from childhood vaccines, found no decrease in autism following the change [88].

Most vaccines for children 6 years of age or younger that had contained thimerosal either no longer contain this preservative or contain only trace amounts—small enough that the FDA considers them "preservative free" [89]. IIV vaccines are now largely in this category, as "preservative-free" preparations of IIV are widely available. For the 2023–2024 season, 91% of IIV vaccines are thimerosal-free or thimerosal-reduced formulations [118].

GBS was associated with a swine flu vaccine in 1976, with an estimated 1 case per 100,000 people vaccinated [21]. Some observational studies since then have found a small increase in GBS cases associated with influenza vaccination, while others have found no link. Whether there is an association between current influenza vaccines and GBS is not known. According to the CDC, based on studies in prior seasons, if an association does exist the risk would likely be low (i.e., one case per 1 million people vaccinated). The IOM conducted a thorough scientific review of this issue in 2003 and concluded that people who received the 1976 swine influenza vaccine had an increased risk for developing GBS. Scientists have multiple theories regarding why this increased risk may have occurred, but the exact reason for this association remains unknown [93].

Clinical trials and the post-licensure monitoring data of three HPV vaccines (two discontinued and one in current use) show that they are safe [107]. Since the licensure of the HPV vaccines, both the CDC and the FDA have monitored HPV vaccine safety through VAERS, VSD, and CISA systems. It should be noted that most of the available data is from the quadrivalent Gardasil formulation, which is no longer available in the United States. A 2009 CDC/FDA report found that the most common adverse events reported to VAERS following vaccination with Gardasil were fainting, swelling at the injection site, headache, and nausea. Seven percent were considered serious. However, no common pattern for serious events has emerged, making it difficult to form theories about causality. GBS was reported but did not appear to occur at a rate above background levels. Blood clots were reported in a small number of patients, most of whom had pre-existing risk factors (e.g., smoking, obesity, use of oral contraceptives). Over the first three years of its use, more than 28 million doses of Gardasil 9 were administered, and 7,244 adverse events were reported to VAERS, of which 3% (217 events) were classified as serious [107].

Healthcare providers can have an influence when parents are concerned or confused about vaccines. For example, in one survey, 28% of parents had some level of uncertainly about vaccines [97]. For those who ultimately decided to allow timely vaccination, assurances or information provided by a healthcare provider were important reasons for the decision.

The Vaccines for Children (VFC) program is designed to help overcome cost as a barrier to childhood vaccination. All of the ACIP-recommended vaccines are available for children enrolled in Medicaid, with VFC covering children through 18 years of age [101]. Children who have no health insurance coverage, children who are underinsured, and children who are American Indian or Alaska Native are also eligible for vaccines through VFC.

Reminding parents to bring their children in for vaccinations is a proven way to increase coverage and is recommended in standards developed by the National Vaccine Advisory Committee and supported by other organizations [102,103]. Reminders need not take up extensive staff time. Mailed reminders have been shown to increase child vaccination rates and so have telephone calls, which may be computer-generated to save work by the office staff [104,105,106]. Outreach should be more intensive for families at high risk of missing appointments [102].

There is evidence that when physicians recommend preventive services, patients are interested in receiving them. For example, 95.1% of patients in a national survey stated that they would accept the herpes zoster vaccination if their doctor recommended it [111]. Standards provided by the National Vaccine Advisory Committee, in cooperation with more than 60 organizations, offer evidence-based methods to help reduce missed opportunities for adults [110]. Providers should assess the vaccination status of all new patients and review vaccination status annually. Pneumococcal vaccination status should be reviewed when patients present for influenza vaccination.

Standing orders for vaccination should be used, based on evidence that they improve adult vaccination coverage in many different settings [110]. Reminder systems for staff can also improve vaccination rates. In one review of studies, use of physician reminder systems, such as chart notations, stickers, and patient lists, improved coverage by a median of 22% [112]. Assessing a practice's success at vaccinating patients who are eligible and reporting the results to staff can also help to improve coverage [110].