Following the Disease: Trends and Outbreaks Drive Subtle Changes to Vaccine Recommendations for Adolescents and Young Adults

EACH YEAR, the Advisory Committee on Immunization Practices (ACIP) develops and updates recommendations on the use of vaccines in U.S. civilians, ultimately informing and providing the Centers for Disease Control and Prevention’s (CDC) public health guidance for the safe use of vaccines. ACIP is composed of medical and public health experts, and its work sets the official routine vaccination schedule for children and adults. Some years, the updates are dramatic (such as adding an entirely new vaccine for a previously unaddressed disease), and sometimes the updates are more targeted (such as adjusting a recommended age range or the wording of a vaccine recommendation’s footnote). In all cases, the committee relies on medical research and surveillance data to inform its decisions.

Recent trends in diseases among adolescents and young adults have fueled some subtle yet significant updates to the vaccine schedule. Many updates have been outbreak-driven, particularly among college campuses (such as the cases of mumps and meningococcal disease). Others reflect vaccine improvements and innovations (HPV and influenza prevention). All are critical in the fight to improve the health of U.S. citizens.

Universities and Mumps: A Major Interruption

Measles has dominated the national headlines due to various outbreaks in 2019. Most prolific has been the outbreak in Washington state, but an additional 11 states have also contributed to the 228 measles cases reported to CDC by the first week of March. And, while these trends are alarming, particularly as measles was declared eliminated in the U.S. in 2000, spikes in measles cases have not spurred much change or updates to standard vaccination recommendations; the best protection against measles remains two doses of the measles-mumps-rubella (MMR, Merck) vaccine. Not surprisingly, for the measles outbreaks mentioned above, most cases have occurred in largely unvaccinated populations.

It is the resurgence in mumps cases and outbreaks beginning in 2015 and 2016 that has caused ACIP to review available vaccine and morbidity data and to determine a third dose of the MMR vaccine is safe and effective and may be applicable for preventing additional disease.

From January 2016 to June 2017, U.S. health departments reported 150 outbreaks and more than 9,200 cases of mumps.¹ Fifty percent of the outbreaks (defined as three or more cases linked by place and time) occurred in university settings.² Two large outbreaks from the University of Iowa and University of Illinois at Urbana-Champaign (UIUC) each involved several hundred university students, and even elite settings like Harvard University did not go unscathed, with officials reporting 66 confirmed cases in the spring of 2016, with additional cases continuing the following school year.³

What makes these mumps outbreaks notable is, contrary to what we are seeing in most measles outbreaks in which cases largely occur in unvaccinated pockets, these outbreaks are occurring despite high two-dose coverage. (UIUC vaccination records showed two-dose MMR vaccination coverage at greater than 97 percent of its student body.⁴ University of Iowa reported 98.1 percent.⁵)

How is this possible? There is no single answer. Mumps is spread through close contact like kissing and sharing drinks, utensils, water bottles or lip balm, and spreads particularly easily in close congregate settings such as dormitories or among members of the same sports team, making universities ripe for mumps transmission. Cases can be infectious up to two days before classic symptoms (swelling of the parotid glands) begin, and the incubation period is quite long — up to 25 days — enabling considerable viral transmission among individuals in close quarters before actual cases are identified and confirmed.

Additionally, all things are not equal within the MMR vaccine, and while the measles vaccine component boasts a high efficacy at 97 percent for two doses,⁶ the mumps component is estimated at 78 percent effective with one dose and 88 percent effective after two doses for preventing mumps.⁷ Studies also show possible waning immunity to mumps as more time passes postvaccination.⁸

Throughout 2017, ACIP reviewed summaries of evidence regarding mumps epidemiology, MMR vaccine effectiveness, duration of protection, immunogenicity and safety for two and three doses, and in October 2017, following a period of public comment, ACIP members unanimously approved a proposed recommendation for a third dose of vaccine during mumps outbreaks. It concluded a third dose provided at least short-term benefit in outbreak settings, with no serious adverse events and benefits outweighing the small risk of vaccine-associated adverse events. Its January 2018 guidance states: “Persons previously vaccinated with two doses of a mumps virus-containing vaccine who are identified by public health authorities as being part of a group or population at increased risk for acquiring mumps because of an outbreak should receive a third dose of a mumps virus-containing vaccine to improve protection against mumps disease and related complications.”²

Several universities have responded to outbreaks with MMR vaccination campaigns — providing evidence for at least three epidemiological studies on the use of a third dose of MMR vaccine in preventing mumps.² And, while data is insufficient at this time to fully characterize the impact of a third dose on reducing the size and duration of mumps outbreaks overall (all finding lower attack rates among third-dose recipients, but only one study showing a statistically significant risk ratio), studies are ongoing to address this question.

A ‘Plan B’ for Preventing Meningococcal Disease

While meningococcal disease is still relatively rare (372 cases reported in the U.S. in 2016), it can be quite devastating, with 10 percent to 15 percent of patients dying, and up to 20 percent of survivors sustaining lifelong disabilities such as arm or leg amputation, hearing loss or neurological damage.⁹ Since 2005, ACIP has recommended adolescents receive routine quadrivalent meningococcal conjugate vaccine covering serogroups A, C, W and Y (MenACWY) for preventing meningococcal disease (adding a booster dose at age 16 in 2010). However, noticeably absent from the quadrivalent vaccine is serogroup B, the current predominant serogroup overall and now accounting for more than half of meningococcal disease cases among persons 16 years to 20 years of age.¹⁰

From January 2013 to May 2018, seven states reported a combined total of 10 university-based meningococcal disease outbreaks, all caused by serogroup B, resulting in 39 cases and two deaths.¹⁰ Previously, CDC had maintained college students in general were not at a higher risk for serogroup B disease than noncollege students of the same age.¹¹ That changed in 2014, when CDC implemented an enhanced meningococcal disease surveillance program, collecting more in-depth data (such as college status) and more routinely typing meningococcal isolates from patients.¹² CDC’s enhanced findings now suggest that while the incidence of serogroup B meningococcal disease in college students remains low, college students age 18 years to 21 years are at increased risk compared to noncollege students.¹¹ (Enhanced findings continued to show no difference in incidence of serogroups C, W and Y among college and noncollege students, likely due to all adolescents routinely receiving MenACWY.¹¹)

Thankfully, the adolescent vaccine platform just got a little wider with the introduction of two brands of meningococcal serogroup B vaccine (MenB): Bexsero (GSK) and Trumenba (Pfizer).¹³ These vaccines differ in formulation from the MenACWY vaccines since they are made of capsular proteins rather than MenACWY’s capsular polysaccharides.

MenB vaccination may be the key to stopping college outbreaks, and it was used in response to all 10 of the serogroup B college outbreaks mentioned above. How much MenB vaccination helped in ending each outbreak has not yet been established. (Five of the 10 outbreaks ended following implementation of MenB vaccination with no new cases, but additional cases did occur at the other five universities. All cases occurred in unvaccinated individuals except in one case, which occurred six days after MenB vaccination, 10 likely too early postvaccination to elicit a fully developed immune response in the individual.¹⁴)

While there is clearly a specific need for MenB vaccination, larger questions remain. Such rare diseases make true vaccine effectiveness trials difficult, and instead licensure is based upon documented serum antibody response — the best measure available at estimating protection. There are also uncertainties regarding how long immunity lasts and when and how booster doses should be administered.¹⁵ MenB vaccine does not appear to affect nasopharyngeal colonization, which is crucial for effective herd immunity.¹⁶ Protection also comes at a financial cost. CDC estimates 15 to 29 cases and two to five deaths could be annually prevented with a routine adolescent MenB vaccine program, but those numbers price MenB at over 20 times greater than the cost for other routinely recommended vaccines (in terms of cost per quality-adjusted life years saved).¹⁷

Still, schools are recommending and in some cases even starting to require MenB. (Fourteen schools are noted to have documented MenB requirements via the Meningitis B Mandate Tracker. 18 Among them is Smith College, which was involved in a serogroup B outbreak in a Five College Consortium in 2017.) So, while at this time MenB vaccine has not been added to the routinely recommended vaccines for all adolescents, ACIP has made MenB a Category B recommendation, allowing for individuals 16 years to 23 years of age to be vaccinated with the MenB series based on individual clinical decision-making.

A New Vaccine for Hepatitis B

The U.S. Department of Health and Human Services (HHS) is reporting low rates of vaccination coverage among adults and increasing rates of injection drug use to be fueling a rise in hepatitis B virus (HBV) infections.¹⁹

And, while HBV transmission among people who inject drugs has always been a concern, the current national opioid epidemic has health officials worried. Massachusetts recently reported an outbreak of hepatitis B associated with injection drug use (noting 2017 acute hepatitis B cases were up 78 percent from 2016 in the state).²⁰ Similarly, Kentucky, Tennessee and West Virginia reported a 114 percent increase in acute HBV infection from 2006 to 2013, with a significant increase in the proportion of cases in which injection drug use was reported between 2010 and 2013.²¹

Despite a routine recommendation for hepatitis B vaccination at birth since the early 1990s,²² data from the 2013 National Health Interview Survey found only 32.6 percent of adults between 19 years and 49 years were fully covered by a complete hepatitis B three-dose vaccine series.²³ CDC surveillance also indicated that in 2015, the acute hepatitis B infection rate in the U.S. increased by 20.7 percent.²⁴

Luckily, another tool has emerged for helping to combat the spread of hepatitis B in young adults. In 2018, ACIP recommended Heplisav-B (Dynavax), a yeast-derived vaccine prepared with a novel immunostimulatory sequence adjuvant, for use in persons 18 years and older. The vaccine joins the other two single antigen hepatitis B vaccines on the market available to adults, Engerix-B (GlaxoSmithKline) and Recombivax HB (Merck). Heplisav-B is notable for requiring only a two-dose series (Engerix-B and Recombivax HB each require three doses), making it an appealing option among young adults with connections to the opioid crisis; fewer required doses mean a greater likelihood of series completion, particularly among a population that might be less likely to engage in routine and preventive care.

Approval of Heplisav-B was based on clinical trials that compared seroprotection rates following two doses of Heplisav-B to rates following three doses of Engerix-B. Seroprotection rates were 90 percent to 95 percent following two doses of Heplisav-B and 65 percent to 81 percent following three doses of Engerix-B among people 18 years to 70 years old. Local reactions (injection site pain, redness and swelling) were similar in frequency to those following Engerix-B.¹⁵

HHS reports new cases of hepatitis B linked to injection drug use are particularly prevalent among adults age 30 years to 49 years who were not vaccinated as children.¹⁹ Heplisav-B comes at a critical juncture as the nation examines the varied sequelae of the opioid epidemic, and it will hopefully serve as a useful tool in reducing outbreaks and spread of this harmful disease.

HPV Vaccine—An Immunization Success Story

HPV vaccine has very quickly evolved since ACIP’s initial routine recommendation for HPV vaccination in girls age 11 years to 12 years in 2007. Since then, vaccine recommendations have also been made for boys (2011), and bivalent Cervarix (2vHPV, GlaxoSmithKline) and quadrivalent Gardasil (4vHPV, Merck) have ceased distribution in the United States, replaced by the more comprehensive Gardasil 9 (9vHPV, Merck). The inactivated 9-valent vaccine contains seven oncogenic (cancer-causing) HPV types (16, 18, 31, 33, 45, 52 and 58) and the two HPV types that cause most genital warts (6 and 11).

The U.S. Food and Drug Administration (FDA) origiinally licensed Gardasil 9 in 2014 for use in males and females age 9 years through 26 years, and notably approved expanded use of Gardasil 9 to include individuals 27 years through 45 years in October 2018.²⁵ This change has initiated discussions at ACIP for potentially updating age recommendation language, as well as harmonizing the recommendations that still differ for males and females (currently, females are recommended vaccine through age 26, males through age 21 unless at higher risk).²⁶ While harmonization for males and females may be an ACIP priority, many studies are showing HPV vaccination of adults becomes less cost-effective as the age of vaccination increases, due to the fact that older adults are likely already infected with HPV. 27 By age 31, 75 percent of women with cervical cancer have already acquired their “causal” HPV.²⁶

Regardless of any imminent changes in response to the updated FDA approval, HPV vaccines continue to show excellent modeling for efficacy and safety, and are proving a potent preventive tool for reducing HPV infections and HPV-associated cancers in adolescents. So much so, data now shows early administration of HPV vaccine reduces the need for all three originally recommended doses.²⁸ Available immunogenicity evidence has shown a two-dose schedule (0, 6-12 months) will have efficacy equivalent to a threedose schedule (0, 1-2 months, 6 months), assuming the HPV vaccination series is initiated before a child’s 15th birthday.²⁹ In other words, the younger a child starts the vaccine series, the better his or her body responds and the more immunity developed (higher geometric mean titers measured). This data led ACIP in October 2016 to recommend a two-dose series for everyone who initiates the series at 9 years to 14 years.²⁸ (A threedose series is still recommended for those initiating the series at 15 years through 26 years of age.)

Influenza Nasal Spray Makes a Comeback

Many are excited about next year’s influenza (flu) vaccine options following a determination by the American Academy of Pediatrics (AAP) to discontinue its preference for the flu shot over nasal spray vaccine for the 2019-20 influenza season. This change comes after a rough couple of years for the nasal spray. Data from several individual U.S. studies had shown live attenuated influenza vaccine (LAIV) nasal spray had demonstrated poor effectiveness and offered less protection against A/H1N1 when compared to injected inactivated influenza vaccine (IIV) since the 2013-2014 season, causing ACIP and AAP to not recommend the nasal spray for the 2016-17 and 2017-18 seasons consecutively.³⁰ In response, LAIV manufacturer, AstraZeneca, reformulated the nasal spray to include a new strain (A/Slovenia) with the goal of producing a better antibody response to circulating A/H1N1 than with the previously utilized (A/Bolivia) strain.

LAIV was brought back to the market for the 2018-2019 season, although not without discord between AAP and ACIP, as LAIV was brought back to the market for the 2018-2019 season, although not without discord between AAP and ACIP, as LAIV was brought back to the market for the 2018-2019 season, although not without discord between AAP and ACIP, as AAP stated a preference for use of the flu shot, indicating nasal spray should really be used only for children who would otherwise not receive a vaccine at all. ACIP did not express a preference between the two.

LAIV’s reformulation seems to have worked in its favor, and following review of data from Europe showing LAIV has been effective against influenza A/H1N1 for children this season, AAP will not express a preference for either nasal spray or injectable vaccine for 2019-20.³¹ ACIP will not make the final call on its flu recommendations until after this article is published, but it has stated it does not anticipate any major changes, meaning AAP and ACIP will likely have similar influenza vaccine recommendations this fall.

Somewhere, needle-adverse patients are cheering.

Small and Large, ACIP Recommendations Provide the Evidence-Based Tools to Help Guide Our Nation’s Health

ACIP immunization recommendations represent the state of the science, and are constantly under review. Immunization successes can shift other diseases into focus, or help to highlight pockets of people at elevated risk and in need of additional considerations. Medical providers questioning appropriate vaccination in an outbreak setting should consult their local health department directly for the most up-to-date data in their area and official guidance on applicable vaccination recommendations. Together, medical providers and public health officials may be able to stop the next outbreak in its tracks.