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Kunal J Rambhia, Milly T Rambhia, Early Bird Gets the Flu: What Should Be Done About Waning Intraseasonal Immunity Against Seasonal Influenza?, Clinical Infectious Diseases, Volume 68, Issue 7, 1 April 2019, Pages 1235–1240, https://doi.org/10.1093/cid/ciy748
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Abstract
Recently published studies highlight the growing evidence for waning immunity within a single influenza season among vaccinated individuals. However, the public health efforts to increase vaccination coverage has resulted in earlier administration of vaccines. We find this approach to be suboptimal, as the benefits of early vaccination could be lost during peak months of influenza activity. Immunity generated by influenza vaccines is a complex scientific issue with many contributing factors. We advocate for a nuanced approach to the seasonal vaccine program- one that considers duration of immunity as much as it considers coverage. As we strive for higher rates of vaccination, we must also improve the efficacy of the vaccine and the public health programs that are responsible for distributing and administering the vaccine.
Hospitalizations from the 2017–18 influenza season were the highest in over a decade. Estimated interim vaccine effectiveness (VE) against the season’s predominant H3N2 strain is only 25% [1], possibly due to virus mutations during egg-based production that influence antigenicity [2], or variation in immunogenicity in certain populations [3]. It is apparent that our seasonal influenza vaccine campaign should be reevaluated, refocused, and potentially redesigned. While the public health community acknowledges that VE can be as low as 39% in a given season [4], the assumption is that those 39%–65% of people for which the vaccine is effective will remain protected for the duration of the influenza season.
A series of new studies challenges that notion. In this perspective, we investigate the phenomenon known as waning intraseasonal immunity, that is, the loss of vaccine-induced protection during a season of influenza while the virus is still actively circulating. Although the root causes of intraseasonal waning immunity are up for debate—and egg adaptation might contribute—the evidence toward its existence is becoming increasingly difficult to ignore. The loss of immunity within vaccinated populations during an influenza season has major public health ramifications. New public health approaches to distribution of influenza vaccine, new vaccine technologies, and improved fundamental understanding of influenza viruses and vaccines are critical to reducing the morbidity, mortality, and economic burden associated with influenza.
UNDERSTANDING WANING IMMUNITY
Most studies that examine influenza VE use a test-negative approach to determine the odds that an individual vaccinated against influenza will contract the disease [5]. The test-negative approach uses confirmed influenza infections among vaccinated individuals and unvaccinated controls to obtain VE, which is defined using the odds ratio of being infected with influenza, usually in the format: VE = (1 − OR) × 100. In the extensive influenza VE literature, few studies have examined time since vaccination as a test variable of VE within a single season. Several studies [6–16] in recent years address this issue and explicate intraseasonal waning immunity among those vaccinated with the seasonal influenza vaccine. These studies apply multivariate linear regression models to calculate VE in various intervals of time since vaccination.
The first questions relating to waning intraseasonal immunity are obvious: is this truly happening, and how quickly does immunity wane? The published studies about waning immunity can be divided into 2 groups: the single year/single strain studies and the multi-year/multi-strain studies (Table 1). In addition to strain, many of these studies also stratify VE by demographics such as age and immune status.
Research Studies That Highlight Waning Intraseasonal Immunity
| Year Published . | Authors . | Season(s) . | Strains . | No. of Participants . | Intervals of VE Studied . | Estimated VE . | Comments . |
|---|---|---|---|---|---|---|---|
| 2015 | Belongia, Van Wormer et al [6] | 2007–08 | H3N2 | 629 | 2-week intervals postvaccination | Adjusted odds of influenza was 1.12 for each 14-day increase postvaccination | Vaccination dates ranged from October 1 to March 4 |
| 2014 | Sullivan, Kelly et al [7] | 2012–13 | H3N2 | 600 | <93 days ≥93 days postvaccination | VE declined from 37% to 18% | |
| 2013 | Kissling, Moren et al [8] | 2011–12 | H3N2 | 1016 | <93 days ≥93 days postvaccination | Adjusted VE dropped from 38% in early season to −1% in late phase | |
| 2013 | Jimenez-Jorge, Larrauri et al [9] | 2011–12 | H3N2 | 351 | 0–3.5 months 3.5–4 months >4 months postvaccination | VE declined from 52% to 40% to 22% at respective intervals studied | Decline in VE was primarily observed in population 65 years and older |
| 2013 | Castilla, Barricarte et al [10] | 2011–12 | H3N2 | 757 | 0–100 days 100–119 days >119 days | VE declined from 61% to 42% to 0% | |
| 2013 | Pebody, Watson et al [11] | 2011–12 | H3N2, B | 3560 | Less than 3 months Greater than 3 months postvaccination | VE declined from 53% to 12% at respective intervals | |
| 2016 | Gherasim, Larrauri et al [12] | 2014–15 | H3N2, B | 5044 | 14–88 days 89–108 days 109–172 days postvaccination | H3N2: Declined from 46% to −12% to −72% Influenza B: Declined from 77% to 62% to −25% | Decline sharper for H3N2 than for influenza B |
| 2016 | Kissling, Moren at al [13] | 2010–11 to 2014–15 | H3N2, B H1N1(pdm09) | 13738(H3N2) 10900 (B) 11385(H1N1) | Early season Late season *variably defined | H3N2 VE dropped to 0% by day 111 post-vaccination | |
| 2016 | Radin, Brice at al [14] | 2010–11 to 2013–14 | Influenza A(H3N2) Influenza B Influenza A(pH1N1) | 1486 | 15–90 days 91–180 days 181–365 days postvaccination | Overall adjusted VE dropped from 54% to 67% during 0–180 days post vaccination to −11% during 181–365 days | |
| 2017 | Ferdinands, Belongia et al [15] | 2011–12 to 2014–15 | H3N2, B, H1N1(pdm09) | 11200 (H3N2) 4100 (H1N1(pdm09)) 5525 (B) | Variable intervals up to 180 days postvaccination | VE declines 7% each month for H3N2 and influenza B and 6%–11% per month for H1N1(pdm09) | |
| 2017 | Puig-Barbera, Schwarz et al [16] | 2011–12 to 2014–15 | H3N2, B, H1N1(pdm09) | 3615 | Early Intermediate Late | Found a lower risk of influenza among late vaccines in 2011/12 and 2014/15 | VE declined in H3N2 dominant seasons |
| Year Published . | Authors . | Season(s) . | Strains . | No. of Participants . | Intervals of VE Studied . | Estimated VE . | Comments . |
|---|---|---|---|---|---|---|---|
| 2015 | Belongia, Van Wormer et al [6] | 2007–08 | H3N2 | 629 | 2-week intervals postvaccination | Adjusted odds of influenza was 1.12 for each 14-day increase postvaccination | Vaccination dates ranged from October 1 to March 4 |
| 2014 | Sullivan, Kelly et al [7] | 2012–13 | H3N2 | 600 | <93 days ≥93 days postvaccination | VE declined from 37% to 18% | |
| 2013 | Kissling, Moren et al [8] | 2011–12 | H3N2 | 1016 | <93 days ≥93 days postvaccination | Adjusted VE dropped from 38% in early season to −1% in late phase | |
| 2013 | Jimenez-Jorge, Larrauri et al [9] | 2011–12 | H3N2 | 351 | 0–3.5 months 3.5–4 months >4 months postvaccination | VE declined from 52% to 40% to 22% at respective intervals studied | Decline in VE was primarily observed in population 65 years and older |
| 2013 | Castilla, Barricarte et al [10] | 2011–12 | H3N2 | 757 | 0–100 days 100–119 days >119 days | VE declined from 61% to 42% to 0% | |
| 2013 | Pebody, Watson et al [11] | 2011–12 | H3N2, B | 3560 | Less than 3 months Greater than 3 months postvaccination | VE declined from 53% to 12% at respective intervals | |
| 2016 | Gherasim, Larrauri et al [12] | 2014–15 | H3N2, B | 5044 | 14–88 days 89–108 days 109–172 days postvaccination | H3N2: Declined from 46% to −12% to −72% Influenza B: Declined from 77% to 62% to −25% | Decline sharper for H3N2 than for influenza B |
| 2016 | Kissling, Moren at al [13] | 2010–11 to 2014–15 | H3N2, B H1N1(pdm09) | 13738(H3N2) 10900 (B) 11385(H1N1) | Early season Late season *variably defined | H3N2 VE dropped to 0% by day 111 post-vaccination | |
| 2016 | Radin, Brice at al [14] | 2010–11 to 2013–14 | Influenza A(H3N2) Influenza B Influenza A(pH1N1) | 1486 | 15–90 days 91–180 days 181–365 days postvaccination | Overall adjusted VE dropped from 54% to 67% during 0–180 days post vaccination to −11% during 181–365 days | |
| 2017 | Ferdinands, Belongia et al [15] | 2011–12 to 2014–15 | H3N2, B, H1N1(pdm09) | 11200 (H3N2) 4100 (H1N1(pdm09)) 5525 (B) | Variable intervals up to 180 days postvaccination | VE declines 7% each month for H3N2 and influenza B and 6%–11% per month for H1N1(pdm09) | |
| 2017 | Puig-Barbera, Schwarz et al [16] | 2011–12 to 2014–15 | H3N2, B, H1N1(pdm09) | 3615 | Early Intermediate Late | Found a lower risk of influenza among late vaccines in 2011/12 and 2014/15 | VE declined in H3N2 dominant seasons |
Abbreviation: VE, vaccine effectiveness.
Research Studies That Highlight Waning Intraseasonal Immunity
| Year Published . | Authors . | Season(s) . | Strains . | No. of Participants . | Intervals of VE Studied . | Estimated VE . | Comments . |
|---|---|---|---|---|---|---|---|
| 2015 | Belongia, Van Wormer et al [6] | 2007–08 | H3N2 | 629 | 2-week intervals postvaccination | Adjusted odds of influenza was 1.12 for each 14-day increase postvaccination | Vaccination dates ranged from October 1 to March 4 |
| 2014 | Sullivan, Kelly et al [7] | 2012–13 | H3N2 | 600 | <93 days ≥93 days postvaccination | VE declined from 37% to 18% | |
| 2013 | Kissling, Moren et al [8] | 2011–12 | H3N2 | 1016 | <93 days ≥93 days postvaccination | Adjusted VE dropped from 38% in early season to −1% in late phase | |
| 2013 | Jimenez-Jorge, Larrauri et al [9] | 2011–12 | H3N2 | 351 | 0–3.5 months 3.5–4 months >4 months postvaccination | VE declined from 52% to 40% to 22% at respective intervals studied | Decline in VE was primarily observed in population 65 years and older |
| 2013 | Castilla, Barricarte et al [10] | 2011–12 | H3N2 | 757 | 0–100 days 100–119 days >119 days | VE declined from 61% to 42% to 0% | |
| 2013 | Pebody, Watson et al [11] | 2011–12 | H3N2, B | 3560 | Less than 3 months Greater than 3 months postvaccination | VE declined from 53% to 12% at respective intervals | |
| 2016 | Gherasim, Larrauri et al [12] | 2014–15 | H3N2, B | 5044 | 14–88 days 89–108 days 109–172 days postvaccination | H3N2: Declined from 46% to −12% to −72% Influenza B: Declined from 77% to 62% to −25% | Decline sharper for H3N2 than for influenza B |
| 2016 | Kissling, Moren at al [13] | 2010–11 to 2014–15 | H3N2, B H1N1(pdm09) | 13738(H3N2) 10900 (B) 11385(H1N1) | Early season Late season *variably defined | H3N2 VE dropped to 0% by day 111 post-vaccination | |
| 2016 | Radin, Brice at al [14] | 2010–11 to 2013–14 | Influenza A(H3N2) Influenza B Influenza A(pH1N1) | 1486 | 15–90 days 91–180 days 181–365 days postvaccination | Overall adjusted VE dropped from 54% to 67% during 0–180 days post vaccination to −11% during 181–365 days | |
| 2017 | Ferdinands, Belongia et al [15] | 2011–12 to 2014–15 | H3N2, B, H1N1(pdm09) | 11200 (H3N2) 4100 (H1N1(pdm09)) 5525 (B) | Variable intervals up to 180 days postvaccination | VE declines 7% each month for H3N2 and influenza B and 6%–11% per month for H1N1(pdm09) | |
| 2017 | Puig-Barbera, Schwarz et al [16] | 2011–12 to 2014–15 | H3N2, B, H1N1(pdm09) | 3615 | Early Intermediate Late | Found a lower risk of influenza among late vaccines in 2011/12 and 2014/15 | VE declined in H3N2 dominant seasons |
| Year Published . | Authors . | Season(s) . | Strains . | No. of Participants . | Intervals of VE Studied . | Estimated VE . | Comments . |
|---|---|---|---|---|---|---|---|
| 2015 | Belongia, Van Wormer et al [6] | 2007–08 | H3N2 | 629 | 2-week intervals postvaccination | Adjusted odds of influenza was 1.12 for each 14-day increase postvaccination | Vaccination dates ranged from October 1 to March 4 |
| 2014 | Sullivan, Kelly et al [7] | 2012–13 | H3N2 | 600 | <93 days ≥93 days postvaccination | VE declined from 37% to 18% | |
| 2013 | Kissling, Moren et al [8] | 2011–12 | H3N2 | 1016 | <93 days ≥93 days postvaccination | Adjusted VE dropped from 38% in early season to −1% in late phase | |
| 2013 | Jimenez-Jorge, Larrauri et al [9] | 2011–12 | H3N2 | 351 | 0–3.5 months 3.5–4 months >4 months postvaccination | VE declined from 52% to 40% to 22% at respective intervals studied | Decline in VE was primarily observed in population 65 years and older |
| 2013 | Castilla, Barricarte et al [10] | 2011–12 | H3N2 | 757 | 0–100 days 100–119 days >119 days | VE declined from 61% to 42% to 0% | |
| 2013 | Pebody, Watson et al [11] | 2011–12 | H3N2, B | 3560 | Less than 3 months Greater than 3 months postvaccination | VE declined from 53% to 12% at respective intervals | |
| 2016 | Gherasim, Larrauri et al [12] | 2014–15 | H3N2, B | 5044 | 14–88 days 89–108 days 109–172 days postvaccination | H3N2: Declined from 46% to −12% to −72% Influenza B: Declined from 77% to 62% to −25% | Decline sharper for H3N2 than for influenza B |
| 2016 | Kissling, Moren at al [13] | 2010–11 to 2014–15 | H3N2, B H1N1(pdm09) | 13738(H3N2) 10900 (B) 11385(H1N1) | Early season Late season *variably defined | H3N2 VE dropped to 0% by day 111 post-vaccination | |
| 2016 | Radin, Brice at al [14] | 2010–11 to 2013–14 | Influenza A(H3N2) Influenza B Influenza A(pH1N1) | 1486 | 15–90 days 91–180 days 181–365 days postvaccination | Overall adjusted VE dropped from 54% to 67% during 0–180 days post vaccination to −11% during 181–365 days | |
| 2017 | Ferdinands, Belongia et al [15] | 2011–12 to 2014–15 | H3N2, B, H1N1(pdm09) | 11200 (H3N2) 4100 (H1N1(pdm09)) 5525 (B) | Variable intervals up to 180 days postvaccination | VE declines 7% each month for H3N2 and influenza B and 6%–11% per month for H1N1(pdm09) | |
| 2017 | Puig-Barbera, Schwarz et al [16] | 2011–12 to 2014–15 | H3N2, B, H1N1(pdm09) | 3615 | Early Intermediate Late | Found a lower risk of influenza among late vaccines in 2011/12 and 2014/15 | VE declined in H3N2 dominant seasons |
Abbreviation: VE, vaccine effectiveness.
The evidence in the single year/single strain studies pointed to a complete loss in VE within a single season as early as 90 days after vaccination to as late as 160 days after vaccination. Despite the variable intervals studied and disparate multivariate models used, some common themes emerged. These include the potential that waning immunity is more prominent in elderly populations and that H3N2 and B subtypes are more susceptible to waning immunity than H1N1(pdm09). The reason for seemingly more durable protection against the H1N1(pdm09) subtype is perhaps due to a better match of vaccine strain to circulating strains and due to less antigentic drift in H1N1(pdm09) subtypes [17].
MULTI-YEAR ANALYSES
Several peer-reviewed studies examined the intraseasonal duration of VE using data from multiple years and also studied VE against multiple strains of the virus. Ferdinands et al published a study in December 2016 in Clinical Infectious Diseases that examined VE over the 4 flu seasons from 2011 to 2015 [15]. The authors found a rate of decline of VE of 6%–11% per month after vaccination for influenza type B and influenza A(H1N1)pdm09 subtype and a rate of 7% for the H3N2 subtype. VE reaches 0 in as few as 5 months after vaccination for H3N2 and influenza type B. There was no interaction between time since vaccination and age group for any type/subtype, although in subjects <60 years old there was a trend toward higher VE against influenza A(H1N1)pdm09 and lower VE against influenza B virus infection.
Radin et al published a study in July 2016 in Vaccine that examined the 4 flu seasons from 2010 to 2014 [14]. In this study, VE was evaluated at 0–3 months, 3–6 months, and 6–12 months after vaccination. Although VE ranged from 54% to 70% for the first 6 months, there were dramatic declines in the 6–12 month group. Declines were observed in both the live attenuated and inactivated vaccine formulations, across multiple age groups, and for multiple types/subtypes of the virus. Declines were observed in 3 of the 4 years studied. Declines were not significant in the 25+ age group or for the H1N1pdm09 subtype.
Kissling et al published a study in April 2016 in Eurosurveillance that examined pooled data from the 2010 to 2014 flu seasons in a multi-center analysis to test for waning intraseasonal immunity [13]. VE for H3N2 subtype declined to 0 after 111 days postvaccination, and VE for influenza type B declined from 70.7% to 21.4% after the end of the season. VE for H1N1pdm09 remained above 50%.
Young et al recently published a meta-analysis that examined data across 14 studies and measured VE in 2 groups: 15–90 days after vaccination and 91–180 days after vaccination. This analysis found statistically significant decline in VE against subtype A/H3 and type B influenza. Decline in VE was also observed for subtype A/H1; however, these were not statistically significant [18].
These studies all reach the same conclusion: VE declines after vaccination and does so perhaps more rapidly than previously thought, particularly for A/H3N2 and B subtypes. Many factors affect influenza VE, including age, prior vaccination, prior infection, antigentic drift, and decline of HA/NA titers. However, waning intraseasonal immunity appears to be a real phenomenon and if an individual was vaccinated in August—when advertising campaigns for the vaccine begin—he or she may be susceptible to the influenza virus by January or February, months with maximal infection rates.
INSIGHTS THROUGH ADDITIONAL RESEARCH
The prospect that a vaccine administered in August loses effectiveness in as little as 3 or 4 months is troubling. However, additional data are needed to further understand waning intraseasonal immunity. In particular, how immunity wanes among different age groups and populations should be better described. Waning immunity has been described in specific immunocompromised populations, including individuals infected with human immunodeficiency virus (HIV). Glinka et al reported on the increased incidence of influenza or influenza-like illness in HIV-infected individuals vaccinated with standard vaccine earlier in the season (prior to mid-November) than those vaccinated late (after mid-November) [19]. Strategies including 2-dose vaccine and high-dose vaccine have both demonstrated higher levels of seroprotection in this population. Additionally, the elderly and children are vulnerable populations, but the mechanism by which waning immunity occurs in these demographics is likely different. Current vaccines target the hemagglutinin “H” (HA) and neuraminidase “N” (NA) membrane proteins on the surface of the flu virus, stimulating a humoral response. Young children are less likely to be primed by natural infection and have immature immune systems, whereas elderly patients have some degree of immunosenescence. The influenza virus stimulates a cellular response in older adults and changes in T-cell function may affect protection, despite adequate antibody titers. As such, measures of cellular immunity may better estimate vaccine protection in the elderly, compared to conventional antibody titer assays [6]. In addition, variance in waning immunity amongst the different vaccine formulations and for the four vaccine strains should also be studied in more detail. As mentioned above, VE is dependent on many factors, and it is critical to understand waning immunity in relation to these other factors.
THE PUBLIC HEALTH CHALLENGES
Although these questions are studied further, there is an opportunity and a need to reassess the public health approach to seasonal influenza vaccination. Practically speaking, an individual who is vaccinated early in the influenza season may not be protected throughout the entirety of the influenza season. As their immunity declines, they may become susceptible to the virus during the peak months of spread. The implications of this phenomenon are important to consider. As the public health community prioritizes early vaccination to maximize the total number of individuals that receive the vaccine and avoid missed opportunities to vaccinate, the millions of people who are vaccinated in August and September may be at risk by January or February, historically when influenza season peaks.
In the current approach, vaccine strains are selected in February for the Northern Hemisphere and in September for the Southern Hemisphere based on what viruses are circulating in the opposite hemisphere. Once vaccine strains are selected, vaccine is manufactured in advance of the respective winter flu seasons. In the Northern Hemisphere, vaccine becomes available as soon as August. Current recommendations in the United States are for anyone older than 6 months to receive a yearly seasonal vaccine, with emphasis on pregnant women, the immunocompromised, and elderly populations. The question is, if immunity lasts for a much shorter time than previously thought, what are the changes that can be made to the seasonal vaccination program?
NO CHANGE IN GUIDANCE
The Advisory Committee on Immunization Practices (ACIP) advises that delaying vaccination is unwise because of the possible loss of opportunity to vaccinate as well as the possibility of localized outbreaks [20]. During the past 10 years, the ACIP has expanded its recommended target groups from those most likely to become critically ill or die from influenza infection, that is, the elderly, immunocompromised, and pregnant women, to all individuals 6 months and older. The combined effects of the 2009 pandemic and the need to vaccinate almost the entire population has also contributed to the vaccination of individuals earlier in the year. Many factors—early pharmacy marketing campaigns, expanded scopes of practice, expanded populations recommended to be vaccinated—have led to immunization at a less-than-ideal time.
The ACIP recommendations for the 2017/18 flu season refer to the studies of waning immunity that examine a single year and single subtype (H3N2) and point to small sample sizes and inconsistent results with respect to age. They hesitate to draw conclusions based on the data available at the time of publication of their recommendations. However, the 3 multi-year studies and recent meta-analysis study provide more convincing evidence of the problem across multiple vaccine formulations and multiple types/subtypes of influenza. The evidence for waning intraseasonal immunity is growing. It is possible that early vaccinations have little protective value during peak months of the flu season.
OPTIMIZING THE CALENDAR
A stronger understanding of immunity decline is essential to maximizing benefit and timing of vaccine administration. Since 2007, the ACIP has recommended seasonal influenza vaccination as soon as vaccine is available. The presence of both a seasonal and pandemic vaccine in 2009 reinforced the promotion of early vaccination against seasonal influenza, as the seasonal trivalent vaccine was available and plentiful during a time when interest in being vaccinated was high. Substantial quantities of the monovalent pandemic vaccine were not available until late October. A side effect of the pandemic was the expansion of scope of practice of pharmacists to be able to vaccinate and the increasing accessibility of flu vaccines and retail pharmacies [21]. In the years since the 2009 pandemic, seasonal vaccination programs have started earlier—vaccine is available as early as July. Table 2 shows the influenza vaccine coverage by season for each Health and Human Services region and entire United States through the month of September, as well as cumulative coverage by season in the United States. Vaccine coverage through September accounted for on average 20% of the cumulative coverage each season (excluding the current season). If many of these doses are administered early in the season, those who receive them may become susceptible to influenza by January or February. Partial or total loss of immunity amongst these individuals would have a major impact on the spread of the disease, the associated illness and death, and the economic burden that flu has every year. The goal of the seasonal vaccine should be to protect the most people as possible for the duration of the season. Improved accuracy in influenza forecasting, in addition to better understanding of waning immunity, may guide in optimizing vaccination schedules.
Influenza Coverage (%) for Persons >6 Months Through September
| Influenza Season . | 2016–17 . | 2015–16 . | 2014–15 . | 2013–14 . | 2012–13 . | 2011–12 . | 2010–11 . | 2009–10 . |
|---|---|---|---|---|---|---|---|---|
| Region 1 | 10.4 | 9.0 | 9.5 | 9.6 | 9.4 | 8.6 | 7.9 | 8.9 |
| Region 2 | 11.4 | 10.2 | 10.3 | 10.4 | 9.6 | 8.9 | 7.9 | 7.3 |
| Region 3 | 11.3 | 9.4 | 9.8 | 9.9 | 9.9 | 9.5 | 7.9 | 9.1 |
| Region 4 | 10.1 | 9.2 | 9.2 | 9.2 | 8.8 | 8.3 | 7.4 | 8.2 |
| Region 5 | 9.4 | 8.4 | 8.6 | 8.6 | 8.3 | 8.0 | 7.0 | 8.3 |
| Region 6 | 10.1 | 10.4 | 10.5 | 9.3 | 9.2 | 9.8 | 8.5 | 8.9 |
| Region 7 | 8.8 | 8.4 | 8.5 | 8.3 | 8.2 | 7.9 | 6.8 | 9.0 |
| Region 8 | 8.7 | 8.4 | 7.9 | 8.3 | 8.1 | 8.5 | 7.7 | 8.9 |
| Region 9 | 11.0 | 8.9 | 9.2 | 11.9 | 8.9 | 8.9 | 7.7 | 6.9 |
| Region 10 | 9.0 | 8.8 | 8.9 | 7.8 | 7.9 | 6.4 | 6.2 | 7.6 |
| United States (coverage through September) | 10.2 | 9.2 | 9.4 | 9.4 | 8.9 | 8.6 | 7.6 | 8.2 |
| United States (cumulative season coverage) | 46.8 | 45.6 | 47.1 | 45.9 | 44.7 | 41.8 | 43.0 | 47.8 |
| Influenza Season . | 2016–17 . | 2015–16 . | 2014–15 . | 2013–14 . | 2012–13 . | 2011–12 . | 2010–11 . | 2009–10 . |
|---|---|---|---|---|---|---|---|---|
| Region 1 | 10.4 | 9.0 | 9.5 | 9.6 | 9.4 | 8.6 | 7.9 | 8.9 |
| Region 2 | 11.4 | 10.2 | 10.3 | 10.4 | 9.6 | 8.9 | 7.9 | 7.3 |
| Region 3 | 11.3 | 9.4 | 9.8 | 9.9 | 9.9 | 9.5 | 7.9 | 9.1 |
| Region 4 | 10.1 | 9.2 | 9.2 | 9.2 | 8.8 | 8.3 | 7.4 | 8.2 |
| Region 5 | 9.4 | 8.4 | 8.6 | 8.6 | 8.3 | 8.0 | 7.0 | 8.3 |
| Region 6 | 10.1 | 10.4 | 10.5 | 9.3 | 9.2 | 9.8 | 8.5 | 8.9 |
| Region 7 | 8.8 | 8.4 | 8.5 | 8.3 | 8.2 | 7.9 | 6.8 | 9.0 |
| Region 8 | 8.7 | 8.4 | 7.9 | 8.3 | 8.1 | 8.5 | 7.7 | 8.9 |
| Region 9 | 11.0 | 8.9 | 9.2 | 11.9 | 8.9 | 8.9 | 7.7 | 6.9 |
| Region 10 | 9.0 | 8.8 | 8.9 | 7.8 | 7.9 | 6.4 | 6.2 | 7.6 |
| United States (coverage through September) | 10.2 | 9.2 | 9.4 | 9.4 | 8.9 | 8.6 | 7.6 | 8.2 |
| United States (cumulative season coverage) | 46.8 | 45.6 | 47.1 | 45.9 | 44.7 | 41.8 | 43.0 | 47.8 |
Regional analyses reflect predefined Health and Human Services regions. Data gathered from Centers for Disease Control and Prevention Seasonal Influenza Vaccine FluVax website.
Influenza Coverage (%) for Persons >6 Months Through September
| Influenza Season . | 2016–17 . | 2015–16 . | 2014–15 . | 2013–14 . | 2012–13 . | 2011–12 . | 2010–11 . | 2009–10 . |
|---|---|---|---|---|---|---|---|---|
| Region 1 | 10.4 | 9.0 | 9.5 | 9.6 | 9.4 | 8.6 | 7.9 | 8.9 |
| Region 2 | 11.4 | 10.2 | 10.3 | 10.4 | 9.6 | 8.9 | 7.9 | 7.3 |
| Region 3 | 11.3 | 9.4 | 9.8 | 9.9 | 9.9 | 9.5 | 7.9 | 9.1 |
| Region 4 | 10.1 | 9.2 | 9.2 | 9.2 | 8.8 | 8.3 | 7.4 | 8.2 |
| Region 5 | 9.4 | 8.4 | 8.6 | 8.6 | 8.3 | 8.0 | 7.0 | 8.3 |
| Region 6 | 10.1 | 10.4 | 10.5 | 9.3 | 9.2 | 9.8 | 8.5 | 8.9 |
| Region 7 | 8.8 | 8.4 | 8.5 | 8.3 | 8.2 | 7.9 | 6.8 | 9.0 |
| Region 8 | 8.7 | 8.4 | 7.9 | 8.3 | 8.1 | 8.5 | 7.7 | 8.9 |
| Region 9 | 11.0 | 8.9 | 9.2 | 11.9 | 8.9 | 8.9 | 7.7 | 6.9 |
| Region 10 | 9.0 | 8.8 | 8.9 | 7.8 | 7.9 | 6.4 | 6.2 | 7.6 |
| United States (coverage through September) | 10.2 | 9.2 | 9.4 | 9.4 | 8.9 | 8.6 | 7.6 | 8.2 |
| United States (cumulative season coverage) | 46.8 | 45.6 | 47.1 | 45.9 | 44.7 | 41.8 | 43.0 | 47.8 |
| Influenza Season . | 2016–17 . | 2015–16 . | 2014–15 . | 2013–14 . | 2012–13 . | 2011–12 . | 2010–11 . | 2009–10 . |
|---|---|---|---|---|---|---|---|---|
| Region 1 | 10.4 | 9.0 | 9.5 | 9.6 | 9.4 | 8.6 | 7.9 | 8.9 |
| Region 2 | 11.4 | 10.2 | 10.3 | 10.4 | 9.6 | 8.9 | 7.9 | 7.3 |
| Region 3 | 11.3 | 9.4 | 9.8 | 9.9 | 9.9 | 9.5 | 7.9 | 9.1 |
| Region 4 | 10.1 | 9.2 | 9.2 | 9.2 | 8.8 | 8.3 | 7.4 | 8.2 |
| Region 5 | 9.4 | 8.4 | 8.6 | 8.6 | 8.3 | 8.0 | 7.0 | 8.3 |
| Region 6 | 10.1 | 10.4 | 10.5 | 9.3 | 9.2 | 9.8 | 8.5 | 8.9 |
| Region 7 | 8.8 | 8.4 | 8.5 | 8.3 | 8.2 | 7.9 | 6.8 | 9.0 |
| Region 8 | 8.7 | 8.4 | 7.9 | 8.3 | 8.1 | 8.5 | 7.7 | 8.9 |
| Region 9 | 11.0 | 8.9 | 9.2 | 11.9 | 8.9 | 8.9 | 7.7 | 6.9 |
| Region 10 | 9.0 | 8.8 | 8.9 | 7.8 | 7.9 | 6.4 | 6.2 | 7.6 |
| United States (coverage through September) | 10.2 | 9.2 | 9.4 | 9.4 | 8.9 | 8.6 | 7.6 | 8.2 |
| United States (cumulative season coverage) | 46.8 | 45.6 | 47.1 | 45.9 | 44.7 | 41.8 | 43.0 | 47.8 |
Regional analyses reflect predefined Health and Human Services regions. Data gathered from Centers for Disease Control and Prevention Seasonal Influenza Vaccine FluVax website.
ADVANCES IN VACCINE SCIENCE ARE NEEDED
Technical solutions to waning immunity should also be pursued and are likely to come in the form of changes to the vaccine. The most prominent changes that could alleviate waning immunity are:
Use of vaccine adjuvants to boost the immune response. In the United States, only 1 adjuvanted flu vaccine is available for the 65 and older population [22]. As people age, the strength of their immune response to a vaccine may diminish. The use of an adjuvant increases immune response so that they will still be protected by immunization. The more widespread use of an adjuvant in vaccines for the remainder of the population would increase the production of protective antibodies. The higher concentration of these protective antibodies, the longer it will take for immunity to wane.
Use of 2-dose vaccines. A second possible change is to introduce a biannual vaccine schedule for susceptible populations. If VE is diminished after 3–5 months, a booster dose may confer supplemental protection for the remainder of the season, particularly for those vaccinated in August or September. Although revaccination is not currently recommended by the ACIP, an effective mid-flu-season booster could alleviate the worry of missed opportunity while conferring longer-term protection. A 2017 study conducted by Tan et al in Vaccine showed 2-dose vaccination in healthy subjects with the inactivated 2009 pandemic H1N1 (2009-pH1N1) vaccine demonstrated significant correlation between HA-specific T-cell responses and hemagglutination inhibition antibody titers, suggesting a priming role of HA-specific T cells for humoral immune response [23].
From a public health practice standpoint, 2 doses are recommended for individuals 6 months to 8 years old who have not been previously vaccinated against influenza, with at least 4 weeks in between doses. There exists precedent for multiple doses in a season and public adaptation of such a schedule is achievable. Although the focus of public health efforts in influenza is to reach a larger proportion of the population each year, the need to confer protection for the duration of the season is equally important. Thus, an effective second dose should be as high a priority as immunizing as many people as possible with an initial dose. The appropriate schedule and dose of antigen of a vaccine and booster would need to be resolved by clinical trials.
Use of a high-dose vaccine. A high-dose flu vaccine is available for the 65 and older population and uses 4 times the antigen used in a regular dose vaccine. The logic behind a high-dose vaccine for the elderly is the same as it is for use of adjuvants. The same principle therefore applies to the expanded use of high-dose vaccines to prevent waning immunity, as the reported literature demonstrates its occurrence across multiple age groups.
Improvements to the manufacturing process to eliminate egg-adaptation and improve strain matching. The 6- to 9-month time frame after the vaccine strains are selected to the delivery of vaccines to consumers is long enough for significant genetic drift of the viruses to occur. Poor match between the vaccine strain and the strains that circulate in the fall and winter contribute to lack of protection and perhaps to waning immunity. By shortening the lead-time needed to prepare the vaccine, strain selection could also be delayed. New technologies that reduce the time to produce the vaccine, such as cell-based antigen production, are being used, but the vast majority of antigen is still produced in chicken eggs. During this step, viruses used to produce vaccine antigen undergo critical changes that may dampen their immunogenic effect in humans. Egg adaptations of influenza viruses during vaccine manufacturing are at the focus of current criticisms of the suboptimal performance of the influenza vaccine [2, 24]. Growth of antigen in chicken eggs is furthermore a rate-limiting step, which necessitates the long lead-time between strain selection and vaccine availability. The effects of antigen mismatch due to adaptive mutations to increase attachment to egg cells are not fully elucidated. However, we do know that most adaptive mutations are in the hemagglutinin protein, which acts as a viral attachment factor. Zost et al determined that the antibodies produced by both human and animal models exposed to the current egg-adapted H3N2 vaccine strain poorly neutralize H3N2 viruses that circulated during the 2016–17 influenza season [25]. We need to improve vaccine strain selection and move beyond egg-based manufacturing; newer manufacturing methods may allow for delayed strain selection and better matching.
Development of a vaccine against a conserved antigen that is not subject to yearly genetic drift. As discussed, current vaccines target the HA and NA membrane proteins on the surface of the flu virus. These proteins undergo natural mutations in their genetic and amino acid sequences as they replicate, which often render previous vaccines ineffective. A “universal” flu vaccine that targets a conserved part of the virus that does not mutate as often or as rapidly would be a game changer. In October 2017, the National Institute of Allergy and Infectious Diseases hosted a workshop to outline the goals and strategy to develop a universal influenza vaccine [26]. This effort should be prioritized with appropriate funding levels to ensure near-term success.
ROOM FOR NUANCE, NOT FOR INACTION
The public health program around seasonal flu vaccine is a large one, with many nuances. There is a great deal of variety in the available vaccines and how they are delivered. The time is now to acknowledge the evidence that points to loss of immunity in individuals who receive the vaccine early in the season—and make the appropriate changes to better protect individuals and populations. Much has been invested in the public health approach to seasonal influenza and it is critical to maximize the value of these investments by incorporating new knowledge around waning immunity into better strategies for vaccination.
Note
Potential conflicts of interest. Both authors: No reported conflicts. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References
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