Marilyn Bulloch, PharmD, BCPS

Protection against circulating influenza viruses is dependent on antibody titers to antigenically similar strains obtained via natural, or vaccine induced immunity.

 Most humans have high antibody titers against strains of influenza viruses encountered in early childhood and exposures at young ages influence how an individual reacts to antigenically distinct strains later on in life.

 indicates that adults born in the 1960s and 1970s may be less able to produce neutralizing antibodies to modern H3N2 strains, and subsequently middle aged patients may be continuously susceptible to Influenza A (H3N2) viruses.

Influenza A (H3N2) first infected humans in the late 1960s.

 They have evolved significantly in the past 5 decades. Since 2014, an antigenically drifted descendant of the first 1968 H3N2 strain known as clade 3c2.A H3N2 viruses has circulated in high levels globally. These viruses uniquely contain a key glycosylation site that shields HA antigenic site B, the major target of neutralizing antibodies. They are also capable of producing a high flu-related morbidity and mortality burden. In the 2017-18 flu season alone, these influenza viruses were responsible for more than 800,000 hospitalizations and more than 60,000 deaths in the United States.

 The fact that 2c2.A H3N2 viruses were dominate in the 2017-18 season may seem surprising because they also were the most common strains in the 2014-15 and 2016-17 seasons, and it would be reasonably expected that many people would have developed immunity against them.

The study authors collected serological samples from different aged individuals in the summer months prior to the 2017-18 influenza season.

 These investigators then characterized antibodies from patients with confirmed 3c2.A H3N2 infections prior to the 2017-18 flu season to see if antibodies would be effective in neutralizing H3N2 viruses circulating in the subsequent 2017-18 season (referred to as 3c2.A2). There were 3 amino acid substitutions seen on the HA of the 3c2.A2 H3N2 viruses compared to the HA of the 3c2.A H2N2 viruses. Over 89% of study patients aged 4 years and older had HA ELISA-reactive antibodies to 3c2.A and 3c2.A2. All but 3 of those who did not were under the age of 4 years and were thought not to have been previously exposed to H3N2 virus.

The study found that children aged 3-10 years had the highest levels of neutralizing antibodies for the viruses. It also showed that most middle-aged adults did not have detectable neutralizing antibody titers against 3c2.A or 3c2.A2 H3N2 viruses. In fact, the lowest titers were measured in patients born in 1967, a year before H3N2 introduction into human circulation. It should also be noted that there did not seem to be any significant HA antigenic changes between the 2014-15 3c2.A and 2017-18 3c2.A2 strains, which usually results in at least some immunity after exposure.

The authors contend that childhood infections that current middle-aged adults experienced in the 1960s and 1970s primed antibody responses that are reactive, but not neutralizing against modern 3c2.A H3N2 viruses. In short, people could produce non-neutralizing antibodies that could bind to the viruses’ HA but did not prevent infection.

The authors followed up on their findings by measuring HA and NA antibodies in a small sample of adults born between 1963 and 1979 before and after confirmed 3c2A H3N2 infection in the 2014-15 season.

 They found that HA ELISA antibody titers increased in serum 4-8 months after infection in most individuals, but neutralizing titers remained low. They also found that 3c2A neuraminidase (NA) antibodies increased but did not respond well to the antigenically drifted 3c2A2 NA from the 2017-18 season.

While the exact reason for the decreased immune response in middle-aged adults remains unclear, these findings suggest that this patient population may be continuously susceptible to the 3c2A H3N2 infection, even with immunization. It also provides some insight into the high infection rates of adults during seasons when H3N2 is the dominant circulating strain and why 3c2A viruses continue to circulate despite minimal to no antigenic drift. The study also raises questions about the existence of other age-related immune responses.

Further and larger studies are needed to fully evaluate immunity among different aged groups and birth years. Data from such studies could lead to a significant breakthrough in our understanding of immunity and subsequently change our influenza prevention approach.

1. Centers for Disease Control and Prevention. Immunogenicity, efficacy, and effectiveness of influenza vaccines. Accessed May 25, 2021. 

https://www.cdc.gov/flu/professionals/acip/immunogenicity.htm

2. Fonville JM et al. Antibody landscapes after influenza virus infection or vaccination. 

3. Gouma S, Kim K, Weirick ME, et al. Middle-aged individuals may be in a perpetual state of H3N2 influenza virus susceptibility. 

4. Allen JD, Ross TM. H3N2 influenza viruses in humans: viral mechanisms, evolution, and evaluation. 

5. Centers for Disease Control and Prevention. Estimated influenza illnesses, medical visits, hospitalizations, and deaths in the United states – 2017-2018 influenza season. Accessed May 25, 2021. 

https://www.cdc.gov/flu/about/burden/2017-2018.htm

Articles

While the exact reason for the decreased immune response in middle-aged adults remains unclear, these findings suggest that this patient population may be continuously susceptible to the 3c2A H3N2 infection, even with immunization. 

Ability to Produce immunity to Influenza A H3N2 Called Into Question for Certain Adults

The 2020-2021 influenza season was strikingly quiet. Cumulative positivity between September 27, 2020 and May 15, 2021 was 0.2%, a rate substantially lower than the 17% average positivity for the 3 previous seasons.

 Although some have argued that positive tests were reduced due to a lack of testing, testing for influenza in North America was consistent with previous years.2 More likely, the low infection rate is the credit of a combination of social distancing, face masks, and vaccinations.

Although the virus did not pose its usual seasonal burden, it was not eradicated. The dominant circulating influenza virus varied worldwide. In the United States, tests conducted by clinical laboratories indicate that Influenza B accounted for approximately two-thirds of infections.

 Influenza B was also dominant in China and the Middle East, while Influenza A appeared to be predominate in North Korea and Japan.

When the flu season for the northern hemisphere ends in spring, it begins for the southern hemisphere and runs through September. The southern hemisphere season is considered to precede the northern hemisphere and provided valuable insight on what to expect when flu season returns in October. The southern hemisphere, so far, is also experiencing a substantially calm flu season.

 Although clinically this may sound positive, it also makes preparing for the next flu season in the northern hemisphere more difficult.

With fewer virus specimens, experts say that it is more difficult to identify and characterize the full extent of the circulating influenza viruses’ genetic and antigenic diversity. In animals, the southern hemisphere’s 2021 vaccines have had mixed efficacy in producing antisera that recognizes, and subsequently affords protection against, circulating viruses.

 Though the match in these models seems to be stronger with the Influenza B lineages and circulating strains, there is more inconsistent efficacy with the Influenza A composition. In fact, changes in circulating Influenza A viruses, especially H3N2 strains, led experts to recommend changes to the composition of the 2021-2022 vaccine for the northern hemisphere.

The recommendations for influenza vaccine composition for Fall 2021 were released in February 2021 by the World Health Organization.

 For the second year in a row, the composition of the vaccine will depend on whether it is egg-based or cell-based or recombinant vaccine. However, the different compositions do not necessarily mean that there is a substantial difference in vaccine-produced immunity to circulating strains. According to the World Health Organization, not all viruses are optimal for the different production systems seen with egg-based vaccines versus cell or recombinant based vaccines. To accommodate this, different viruses with similar properties were selected as prototypes for timely vaccine production to ensure adequate supply by Fall 2021.

In 2021-2022, all influenza vaccines, regardless of type, will contain the same lineages of Influenza B, which are unchanged from the 2020-2021 season. This coincides with the matched protection seen in both the northern hemisphere’s 2020-2021 season and the southern hemisphere’s season so far. When lineage has been determined, most Influenza B viruses in 2020-2021 were B/Victoria/2/87 or B/Yamagata/16/88 lineage, which were closely related genetically and antigenically to the strains included in the vaccine. Quadrivalent vaccines will again include B/Washington/02/2019 (B/Victoria lineage)-like virus and B/Phuket/3073/2013 (B Yamagata lineage)-like virus. Trivalent vaccines will only contain the Victoria lineage, but the majority of available vaccines in the United States have transitioned to a quadrivalent composition.

Both strains of Influenza A for the northern hemisphere vaccines will be different from those included last season. Unlike last flu season, they will only differ by the H1N1 component rather than both strains of Influenza A. The H1N1 composition will resemble the current southern hemisphere vaccines’ H1N1 composition. Vaccines that are egg-based will include A/Victoria/2570/2019(H1N1)pdm09-like virus while cell and recombinant-based vaccines will include A/Wisconsin/588/2019 (H1N1)pdm09-like virus. The southern hemisphere’s current H3N2 component (Influenza A/Hong Kong/ 45/2019 (H3N2)-like virus in cell or recombinant-based vaccines and A/Hong Kong/2671/2019 (H3N2)-like virus) is identical to what was included in the northern hemisphere’s vaccines for 2020-2021,but appear to be producing inconsistent efficacy and protection to current circulating strains. As a result, vaccines administered in the fall will contain an updated strain of H3N2, an A/Cambodia/e0826360/2020 (H3N2)-like virus.

It is impossible to predict if the low rates of influenza in the 2020-2021 season will be repeated or serve as an isolated anomaly. The impact of the change in vaccine composition will not be known for almost another year. Eased infection control practices related to COVID-19, such as reduced face mask wearing, will also likely return influenza transmission to its usual potential. Although these measures had a noticeable contribution to the decrease in transmission of the influenza virus, the influenza vaccine remains the best way to protect against the potentially fatal virus.

It is important that patients be encouraged to receive the vaccine, even if Influenza B continues to dominate in the upcoming season, since there is a post-vaccination decline in protective antibodies. This past year has introduced the possibility that influenza season does not have to consistently produce a high health burden. The prevention strategies championed by pharmacists and other health care providers for years, vaccination and practical infection prevention practices demonstrated their capabilities in full force. While it is unlikely that all of the practices employed during the 2020-2021 season for the COVID-19 pandemic will be broadly utilized during future flu seasons, pharmacists can and should continue to champion common-sense preventative strategies such as hand hygiene, staying home when sick, and most importantly, annual influenza vaccination.

Centers for Disease Control and Prevention. FluView. Updated May 15, 2021. Accessed May 25, 2021. 

World Health Organization. Recommended composition of influenza-virus vaccines for use in the 2021-2022 northern hemisphere influenza season. Updated February 26, 2021. Accessed May 25, 2021. 

https://www.who.int/influenza/vaccines/virus/recommendations/2021-22_north/en/

Both strains of Influenza A for the northern hemisphere vaccines will be different from those included last season. 

Influenza Vaccination Updates for the 2021-2022 Season

Originally thought to be a predominantly temporary infection, a growing proportion of patients are experiencing prolonged symptoms from SARS-CoV-2 infection, or “Long COVID”.

Symptoms of Long COVID, which like COVID-19 itself, can be highly varied from patient to patient, but most commonly include fatigue, insomnia, “brain fog”, anxiety, depression, gastrointestinal symptoms, myalgia, and breathlessness.

 Some symptoms extend from the acute infection while others arise later. Researchers and medical professionals do not fully understand the pathophysiological or immunological mechanism behind this unfortunate phenomenon.

Support groups and patient care clinics have been created to help patients who suffer from lasting effects of the virus and large research studies, such as the SARS-CoV-2 Recovery Cohort though NIH, aim to provide more insight into why some patients develop Long COVID and how best to manage it.

 A recent study, not yet published in a peer-reviewed journal, may provide hope for patients via an unexpected source: vaccination.

The study, performed with help from the LongCovidSOS campaign in the United Kingdom (UK), was initially developed to determine if COVID-19 vaccines could worsen symptoms associated with Long COVID. According to the authors, there were anecdotal reports of substantial symptom improvement following vaccination, contrasting with fear that immunization might worsen Long COVID.

A cohort of patients admitted to a single UK hospital between April and May 2020 were recruited for a prospective observational study with follow-up at hospital discharge, 3 months (approximately June-July 2020), and 8 months (approximately December 2020 to January 2021). Over 80% of these patients reported at least 1 ongoing symptom associated with their COVID-19 infection. Within this group, 44 participants who received at least 1 dose of a COVID-19 vaccine were surveyed 1 month following vaccination (approximately January – February 2021) to evaluate Long COVID symptoms. Twenty-two unvaccinated patients in the observational cohort served as matched controls.

At the 8-month follow-up and prior to vaccination, symptom burden was high among all patients. Those in the soon-to-be vaccinated group reporting 159 symptoms, and 91 symptoms were reported in the unvaccinated group.1 A small, but significantly greater, improvement in symptoms occurred in vaccinated patients compared to unvaccinated patients during the same period [37 of 159 (23.2%) vs. 14 of 91 (15.4%); p=0.035].

When differences in scores across all symptoms were combined, 56.7% of individuals in the study experienced symptom improvement after 1 vaccine dose and 24.6% had no change. It is worth noting that 18.7% of patients experienced symptom deterioration which may be concerning. However, the number of patients experiencing deterioration during this period was similar between vaccinated and unvaccinated patients and it does not appear that the immunization contributed to the worsening of any symptoms.

Generally, it appears immunization may improve Long COVID symptoms, but does not appear to exacerbate or worsen them. Almost half of vaccinated patients said the improvements were permanent. Since 72% of patients were within 30 days of vaccination, it is possible that the number of patients experiencing continued symptom improvement was underestimated and follow-up studies are required to determine the long-term impact of immunization on symptom status.

In addition to physical symptom impact, vaccination was also associated with a significant improvement in wellbeing according to the Warwick and Edinburgh Mental Wellbeing scores (p=0.006). The study also suggests that mRNA vaccines may provide more symptom improvement than adenovirus vector vaccines, but the sample size is most likely too small to provide a conclusive comparison.

These study results need to be confirmed in larger studies with diverse patient populations and the mechanism of the impact requires exploration. The study is too small to draw firm associations on the benefit of COVID-19 vaccination on Long COVID symptoms.

 However, it does provide hope for patients who are suffering long after the acute COVID-19 infection resolves and introduces a potential novel role in therapy for these vaccinations beyond infection prevention.

Collins FS. NIH launches new initiative to study “Long COVID”. Updated February 23, 2021. Accessed May 21, 2021. 

https://www.nih.gov/about-nih/who-we-are/nih-director/statements/nih-launches-new-initiative-study-long-covid

Arnold DT, Milne A, Samms E, et al. Are vaccines safe in patients with Long COVID? A prospective observational study. medRxiv.2021;DOI:10.1101/2021.03.11.21253225

Centers for Disease Control and Prevention. Post-COVID Conditions. Updated April 8, 2021. Accessed May 21, 2021. 

https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects.html

Support groups and patient care clinics have been created to help patients who suffer from lasting effects of the virus.

Vaccination May Help Reduce Symptoms of Long COVID

Each April, the National Rosacea Society (NRS) celebrates Rosacea Awareness Month in an effort to increase public awarenss of a condition that affects approximately 16 million people in the United States. Throughout April, the NRS hosts a variety of activities with a goal of educating patients who are experiencing the symptoms of the condition, but not yet diagnosed with Rosacea, to seek evaluation and effective management.

Rosacea is most commonly seen in fair skined individuals, but has been diagnosed in patients of all ethnicities and backgrounds. Women experience symptoms more often than men and symptoms usually appear after the age of 30.

In 2018, the NRS focus will be around new classification standards recently published, the first update to these standards since 2002 and only the second set of classfication standards ever released by the Society. The 2002 classifications focused on common morphologic groupings into subtypes, while the 2017 version emphasizes individual phenotypes based on observable characterisits resulting from environmental of genetic factors. In order to be diagnosed with rosacea, patients should have either fixederythema in the facial center that has a characteristic pattern or phymatous changes such as skin thickening, fibrosis, patulous follicles, rhinophyma (a large red bulbous nose), or glandular hyperplasia. Centrofacial redness intensity may be consistent or may periodically increase and is the most common sign of rosacea.

It is important to rule out other causes of these symptoms, including drug-induced causes such as corticosteroid-induced rosacea or drugs causing lupus erythematosus, before the diagnosis of rosacea is made. These cutanous signs usually appear with at least one diagnositic feature, but the presence of two or more major phenotypes can also be considered diagostic for the condition.

Major phenotypes, or features, listed in the new standard include:

 primarily in the centrofacial area. These should be distinguished from comedones which should be credited to an acne process rather than rosacea. Patients may also experience nodules

 that is frequent and usually prolonged.  Erythema from flushing may be less visually apparent in patients with darker skin tones, but these patients may report subjectively expericing this symptom

 which are widened venules that redlines or patterns on the skin, often in clusters.

, especially lid margin telangiectasis, scleritis, sclerokeratitis, spade-shaped infiltrates in the cornea, or redness on the conjunctiva between the eyelids. 

The 2017 standards also list multiple secondary phenotypes that may occur in patients. These signs and symptoms may include:

, usually on erythematous skin with or without scales.

 that accompanies of follows extended erythema or flusing due to post-capillar extravasation during inflamation and may persist for several days.

 that are not exclusive to rosacea, such as burning, stinging, photosensitivity, foreign object sensation, conjunctivitis, or 'honey crust' and cylindrical collarette accumulation at the eyelash bases.

Diagnosis and subsequent treatment can have a tremendouns impact on patients' quality of life. Untreated or undertreated rosacea has been linked to depression and anxiety. Trigger avoidance, laser therapy, or topical or oral medications directed at symptoms (i.e. clonidine for flushing, antiinflammatories, or artificial tears for occular symptoms ) are all potential treatment options, depending on the severity of the rosacea. Pharmacists who suspect that a patient may be suffering from rosacea should refer them to the primary care physician for evaluation.

Rosacea Awareness Month. National Rosacea Society. 

Gallo RL, Granstein RD, Kang S, et al. Standard classification and pathophysiology of rosacea: The 2017 update by the National Rosacea Society Expert Committee. 

Rosacea Awareness Month to Highlight New Standard Classification and Pathophysiology of This Widely Misunderstood Disorder [news release]. Barrington, IL. National Rosacea Society. February 1, 2018. 

www.rosacea.org/press/rosacea-awareness-month-highlight-new-standard-classification-and-pathophysiology-widely

Rosacea Treatment Algorithms. National Rosacea Society. 

www.rosacea.org/physicians/treatmentalgorithms

In 2018, the National Rosacea Society's focus will be around new classification standards.