Shorts

By Jule Klotter

Influenza Vaccine and Coronavirus

A January 2020 study by Greg G. Wolff looked at the possibility of viral interference in people who received influenza vaccination compared to those who did not. Although flu vaccines may provide some protection against that year’s circulating viral strains, “vaccinated individuals may be at increased risk for other respiratory viruses because they do not receive the non-specific immunity associated with natural infection,” according to Wolff. Wolff used data from the US Department of Defense Global Respiratory Pathogen Surveillance Program (DoDGRS) for the 2017-2018 flu season. DoDGRS contains vaccination status and results from multiplex PCR respiratory pathogen panels for DoD beneficiaries (active duty personnel, their spouses, children, retirees, and others); 6541 in the study were vaccinated and 2928 were not. In this retrospective study, Wolff excluded people with influenza and non-influenza coinfections, those who had multiple specimens taken over the season, and those who tested positive for bacterial infections (Chlamydia pneumoniae, Mycoplasma pneumoniae).

According to Table 5 in his study, a larger percentage of unvaccinated people (n=1299; 44%), compared to vaccinated (n=2050; 31.3%), tested positive for influenza viruses (Influenzas A, Hi1N1, H3N2, B, B Victoria, B Yamagata). The vaccinated population, however, were more likely to test positive for non-influenza virus (OR 1.15; 95% CI, 1.05, 1.27), coronavirus (1.36; 95% CI, 1.14, 1.63), and human metapneumovirus (OR 1.51; CI 95%, 1.20, 190).

The influenza vaccination is being highly promoted this year as a means of decreasing hospitalization rates in the coming season, during which many expect a resurgence of the coronavirus SARS-CoV-2. Noting that Wolff’s findings “have triggered concern that influenza vaccination may detrimentally affect COVID-19 risk,” Canadian researchers conducted their own retrospective study, using data from the community-based Canadian Sentinel Practitioner Surveillance Network that included specimens collected during the 2010-11 to 2016-17 flu seasons. They found “the adjusted OR (odds ratio) for influenza vaccination among coronavirus cases versus coronavirus test-negative controls was 1.4 (95% CI, .85-1.28).” The Canadian group also reported a “methodological problem” in Wolff’s calculation of virus interference odds ratio for the 2017-2018 influenza season (Table 3). Although their study did not find evidence of viral interference, the Canadian researchers say, “population surveillance signals elsewhere suggesting cross-pathogen immunological interactions still warrant immune-epidemiological investigation.”

One study that indicates viral interference is a 2012 double-blind randomized controlled trial, led by Benjamin J. Cowling. Although this study did not find an increased risk of coronavirus after vaccination, it did find increased risk of symptomatic non-influenza respiratory virus infections in children who received an inactivated trivalent influenza vaccine for the 2008-09 flu season: “participants who received [the vaccine] had higher risk of [acute respiratory illness] associated with confirmed non-influenza respiratory virus infection (RR, 4.40; 95% CI, 1.31-14.8)”—primarily rhinoviruses and coxsackie/echoviruses.

Both Wolff’s study and the Canadian study used a test-negative design (TND). The Canadian researchers note that “random variation, bias, and confounding may influence TND findings.” Wolff says this type of study is often used to calculate influenza vaccine effectiveness and the design is based on the assumption that a vaccine cannot affect the risk of other infections: “The virus interference phenomenon goes against the basic assumption of the test-negative vaccine effectiveness study that vaccination does not change the risk of infection with other respiratory illness, thus potentially biasing vaccine effectiveness results in the positive direction.” Perhaps, other study designs should be used to evaluate the flu vaccine’s ability to prevent illness?

Cowling BJ, et al. Increased Risk of Noninfluenza Respiratory Virus Infections Associated with Receipt of Inactivated Influenza Vaccine. Clin Infect Dis. 2012;54(12):1778-83.

Skowronski DM, et al. Influenza Vaccine Does Not Increase the Risk of Coronavirus or Other Noninfluenza Respiratory Viruses: Retrospective Analysis from Canada, 2010-2011 to 2016-2017. Clin. Infect. Dis. 2020.

Wolff GG. Influenza vaccination and respiratory virus interference among Department of Defense personnel during the 2017-2018 influenza season. Vaccine. January 2020; 38:350-354.

Preventing Infectious Respiratory Illness with BCG Vaccine?

Does the Bacillus Calmette-Guérin (BCG) vaccine prevent COVID-19? BCG, which contains live attenuated Mycobacterium bovis, is used to protect against Mycobacterium tuberculosis infection. A single dose, given to infants by intradermal injection or multiple puncture device, reduces the risk of tuberculosis (its primary target); but it also decreases the incidence of non-tuberculosis mycobacterial infections, like leprosy and Buruli ulcer, and respiratory tract infections, according to a review article by Kiddus Yitbarek and colleagues. They say the vaccine provides more protection when given to infants, age three months or younger, before (and not with) the diphtheria-tetanus-pertussis (DTP) vaccine. Yitbarek et al looked at nine studies (dated 2005-2020) that focused on the vaccine’s effect on respiratory tract infections. BCG induces specific T-cell immune response against TB as well as adaptive immunity, which protects against other infections. BCG vaccination also appears to increase the removal of dead cells from the lungs by phagocytes.

While BCG is not on the US CDC vaccine schedule, it is (or was) a consistent part of vaccine programs in other countries for decades. Epidemiologists are reporting that countries with regular BCG vaccination have lower death rates from COVID-19. A study by Luis E. Escobar and colleagues looked at the evidence that BCG protects against severe COVID-19. They collected COVID-19 mortality data (as of April 22, 2020), BCG vaccination data, and potential confounding variables (i.e., income, population size, human density, urbanization, population’s age structure, health and education services, and income). A “coarse analysis” found that percentage of population >65 years, urbanization, and higher Human Development Index (derived from life expectancy, education, and per capita income) “were consistently and positively associated with COVID-19 deaths” In addition, “countries with a strong BCG vaccination policy had significantly lower COVID-19 deaths per million.”

To lessen the effect of confounding factors, Escobar et al performed another analysis that included 22 countries that met the following parameters: “at least one death per million inhabitants, ≥15% of population with an age of 65 y or more, >60% of population living in urban areas, >300 inhabitants per square kilometer, and an HDI of >0.7.” Again, there was a statistically significant inverse association between BCG vaccination and COVID-19 mortality. Germany provided particularly interesting data. Before unification, East and West Germany used different vaccine programs. East Germany, like other Eastern European countries, used BCG vaccine for decades. West Germany added BCG to its schedule later: “In West Germany, those 22 y to 59 y old today were vaccinated, while, in East Germany, those 45 y to 84 y old today received at least one dose of BCG.” Average COVID-19 death rate in eastern German states, as of April 22, was 14.2 deaths per million. The average in western German states was 40.5 deaths per million—2.9-times higher.

In another analysis that compared European countries that are socially similar, the author found “A highly significant linear correlation…between the BCG index and mortality during the first month of the pandemic (r²=0.88; p=8 X 10^-7); indicating that every 10% increase in the BCG index is associated with a 10.4% reduction in COVID-19 mortality.”

Epidemiological evidence cannot prove cause and effect. A randomized double-blind, placebo-controlled clinical trial, with about 10,000 Australian healthcare workers, is being conducted now to see if BCG vaccination prevents severe COVID-19 in adults (NCT04327206). Primary completion is dated June 30, 2021. We can hope that SARS-CoV-2 has largely died out by then, but the clinical trial may provide evidence that BCG has unintended positive effects.

Escobar LE, Molina-Cruz A, Barillas-Mury C. BCG vaccine protection from severe coronavirus disease 2019 (COVID-19). PNAS. July 28, 2020.

Yitbarek K, et al. The effect of Bacillus Calmetter-Guérin (BCG) vaccination in preventing severe infectious respiratory diseases other than TB: Implications for the COVID-19 pandemic. Vaccine. 2020;38:6374-6380.

Elderberry and Respiratory Infections

A 2020 review of five randomized, double-blind controlled clinical studies, involving 936 participants, supports the use of elderberry (Sambucus nigra) preparations to reduce symptom severity and duration in cases of flu and/or common cold. The review authors evaluated the studies for risk of bias using the Cochrane Collaboration Risk of Bias tool. They noted concerns about treatment assignment in two studies, but low risk of bias otherwise. Three low-bias-risk trials (n=399) compared an elderberry extract product (Sambucol syrup in two studies, standardized extract capsules in one) to a placebo. In all three, elderberry treatment reduced illness duration (mean) by about 50%. A trial that compared an elderberry-echinacea product to oseltamivir (Tamiflu) reported similar recovery rates in the two groups and fewer adverse events in the herbal group. Data from the studies indicate that elderberry can reduce severity and duration of fever, headache, nasal congestion, and nasal mucus discharge when the treatment is started within the first 48 hours.

Australian researcher Golnoosh Torabian and colleagues discussed elderberry’s known anti-influenza effects in a 2019 paper. In laboratory tests, Torabian et al showed that elderberry prevents influenza viruses from entering cells and replicating by deactivating viral HA glycoprotein spikes that permit the virus to attach to cell walls. Flavonoids in elderberry stimulate the immune system and production of cytokines, including IL-8, IL-6, and TNF. (There is no strong evidence, as of 2019, that shows elderberry can contribute to a cytokine storm, according to Harnett et al.) And polysaccharides in elderberries stimulate macrophage activity.

An elderberry product might be useful to have on hand during the cold/flu season.

Harnett J, et al. The effects of Sambucus nigra berry on acute respiratory viral infections: A rapid review of clinical studies. Advances in Integrative Medicine. 2019.

Torabian G. Anti-influenza activity of elderberry (Sambucus nigra). J Functional Foods. 2019;54:353-360.

UC Flu Vaccine Mandate Lawsuit

On July 31, 2020, former University of California System President Janet Napolitano issued an executive order mandating flu vaccination for all students, faculty, and employees by November 1, 2020. Failure to comply would result in job loss or removal from school. Faculty and staff can opt out if they work online; religious exemptions are also possible. Students were not given the same accommodations. The executive order affects 510,000 people. The rationale for the mandate is that the vaccine will reduce hospitalizations due to flu—leaving more beds for people with COVID-19. Several organizations, including Physicians for Informed Consent and A Voice for Choice Advocacy, have written to the Board of Regents and the current UC president, asking that they make flu vaccination a recommendation instead of a mandate.

On August 27, Richard Jaffe, Esq., Robert F. Kennedy, Jr., Esq., and Mary Holland, Esq. filed an injunction lawsuit against the Regents of the University of California and the UC president on behalf of two students, one employee, and two faculty members who do not want to be vaccinated. The faculty members are UCLA law professor Frances Olsen and Cindy Kiel, JD, an executive associate vice chancellor at UC-Davis. Kiel oversees research projects at UC-Davis, which includes oversight of ethical issues. The hearing is set for October 14 at the Hayward branch of the Alameda Superior Court.

The plaintiffs’ team also filed a preliminary injunction on September 17 and pointed out the violation of students’ equal protection and First Amendment rights since they were not given the same religious accommodations and online exemptions as faculty and staff. Days later, UC issued a revised executive order that permits online-only students to forgo vaccination and gives all students the ability to ask for religious exemption to the mandate. Rick Jaffe, in his October 1 blog at rickjaffesq.com, says, “The UC has apparently hired outside consultants to function as judges deciding on the bona fides of people seeking a religious accommodation to the flu shot.” Criteria for religious exemption was unknown at that time.

In his September 17 blog, Jaffe has links to the statements being used to support the plaintiffs’ case. I was very surprised to see names I recognized in the list, including international experts like Peter Gøtzsche, MD, co-founder of the Cochrane Collaboration; Thomas Jefferson, MD, the lead author of Cochrane’s 2018 report on flu vaccination; and Peter Doshi, PhD, associate editor at The BMJ (British Medical Journal) who worked with Jefferson on the report. Jaffe’s October 2 blog has links to the statements for the defense.

By the time you read this, the hearing will be over, and results should be in. I’m hoping the right to choose or forgo a medical intervention wins.

Jaffe R. Breaking News! UC Makes a Tactical Retreat with Its New Executive Order, and It’s Good News for Students, (Albeit Temporary and Only for Some students). October 1, 2020.

Jaffe R. The High Priests of the Religion of Vaccinology Circle the Wagons Around the UC Flu Mandate and Recite Their Gospel. October 2, 2020.

Jaffe R. Preliminary Injunction Motion Filed in the UC Flu Mandate Case; Hearing Set for October 145h at 1:30 PM. September 17.