Russell Libby, MD, is an assistant clinical professor of pediatrics at the University of Virginia School of Medicine in Charlottesville, Virginia, and at the George Washington University School of Medicine in Washington, DC.

Russell Libby, MD, FAAP

It is hard to believe that in the fall of 2019, the No. 1 winter viral threat to the health of our communities was influenza. Based on its quasi-predictable genetic markers, we urgently promoted vaccination, stocked up on Clinical Laboratory Improvement Amendments–waived test kits, and prescribed antiviral medications for patients and their families to protect our communities and reduce the potential for spread. Most of us were not prepared for what was coming and how it would dwarf the severity and impact of a viral pandemic that had been the historic standard by which we measured suffering.

COVID-19’s global impact has touched every aspect of our lives and precipitated a redesign of health care as we knew it. The morbidity and mortality seen in the senior and chronically ill populations have not been seen in children, although, as of this writing, hospitalizations for children have been spiking across the United States. It is hard to estimate the incidence and severity from reported data, and the variants and availability of vaccines make it even more so. Before Omicron, 0.1% to 1.8% of children with COVID-19 needed hospitalization, whereas 0.5% to more than 10% of adults (increasing with age) were hospitalized. Less than 0.03% of infected children died; for adults, that rate was about 1% and significantly higher in those over age 65 years. The fatality rate for children is dwarfed by that caused by unintentional accidents.

Hospitalization for influenza and COVID-19 in children has been most notable with specific underlying conditions. A retrospective analysis of 315 laboratory tests confirmed SARS-CoV-2, and 1402 laboratory tests confirmed cases of influenza A and B showed a significant increase in hospitalization for COVID-19 in children who had a neurologic diagnosis with global development delay or seizures (20% vs 8%). COVID-19 and seasonal influenza had similar rates of hospitalization, intensive care unit admission, mechanical ventilation, and duration of ventilator support.

As we became obsessively careful with sanitizers, masks, social distancing, and quarantines, we came to recognize that COVID-19 is very different from influenza. COVID-19 is more contagious and more significant in short- and long-term morbidity yet more variable in its manifestation from asymptomatic to rapidly fatal. Symptoms can be nearly identical and only testing can differentiate, but the overlap seems to stop there, with COVID-19 adding a more diverse menu of symptoms and complications. The Table lists some similarities and differences in symptoms, complications, and the diagnosis and treatment of influenza and COVID-19.

Detecting influenza and COVID-19: Similarities and differences 

Most pediatricians used a fever and fatigue threshold for testing for influenza, but COVID-19 testing is done for anyone, even those with no symptoms. Incidence and outcomes are all local, and following local epidemiological reports is essential for helping to differentiate what is affecting communities, but with COVID-19, vaccination rates, infection precautions such as masks, and social determinants of health can have a disproportionate impact.

We often overlook some of the complicating features that are so infrequent with influenza in kids but can be devastating. A major difference between influenza and COVID-19 is the expectation that, with influenza, once the illness has subsided, the impact of that infectious agent is over, with the secondary infection or organ damage as separate residua. COVID-19, on the other hand, has the potential to directly incite the immune system and can have lingering effects that are disabling and potentially fatal.

When discussing COVID-19 infection with families, pediatricians will often include a caution for the infrequent possibility for multisystem inflammatory syndrome in children (MIS-C), but probably the most common and actionable concern is cardiac, especially for adolescent athletes. (Of note: Since June 2020, there have also been several reported cases of MIS in adults

). We have come to recognize that myocarditis, pericarditis, and rhythm abnormalities are common to both influenza and COVID-19 yet more common, lingering, and possibly more subtle with COVID-19. The immediate focus on COVID-19 has made it more of a concern and promulgated a set of recommendations for screening patients with specific symptoms and a severity-related algorithm and staged return to sports for adolescent athletes. Although the cardiac problems can be associated with influenza or COVID-19 infection, COVID-19 has the added etiologies of MIS-C and an adverse effect of the vaccine, especially in adolescent male patients.

Both the influenza and the COVID-19 messenger RNA vaccines have seen associated with Guillain-Barre syndrome, but not at the frequency seen with actual infection. The incidence after vaccination is rare enough and the public and individual health benefit large enough to recommend vaccination against both.

Certainly, there are so many other areas of overlap, especially as we see new formulations of vaccines that can adapt and generalize antigens that may provide better specificity and immunocompetence. However, for now we continue to deal with a hit-or-miss influenza vaccine and viral mutations that can reduce vaccine effectiveness and, unfortunately, feed the reluctant and refusers with self-justification. The elevation of COVID-19 and its identity as a pandemic magnifies the reality of both our vulnerability and our potential to effectively respond with the development of vaccines and treatments.

1. Accident statistics. Stanford Children’s Health. Accessed January 10, 2021. 

https://www.stanfordchildrens.org/en/topic/default?id=accident-statistics-90-P02853


2. Song X, Delaney M, Shah RK, Campos JM, Wessel DL, DeBiasi RL. Comparison of clinical features of COVID-19 vs seasonal influenza A and B in US children. 

. 2020;3(9):e2020495. doi:10.1001/jamanetworkopen.2020.20495

3. Multisystem inflammatory syndrome in adults (MIS-A). Centers for Disease Control and Prevention. November 13, 2020. Accessed January 10, 2022. 

4. Guillain-Barré syndrome and vaccines. Centers for Disease Control and Prevention. Updated August 25, 2021. Accessed annuary 7, 2021. 

https://www.cdc.gov/vaccinesafety/concerns/guillain-barre-syndrome.html

5. Pilarowski G, Lebel P, Sunshine S, et al. Performance characteristics of a rapid severe acute respiratory syndrome coronavirus 2 antigen detection assay at a public plaza testing site in San Francisco. 

. 2021;223(7):1139-1144. doi:10.1093/infdis/jiaa802

6. Interim guidance for antigen testing for SARS-CoV-2. Centers for Disease Control and Prevention. Update September 6, 2021. Accessed Jan 10, 2022. 2021.


https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.html



7. Interim guidelines for COVID-19 antibody testing. Updated September 6, 2021. Accessed January 10, 2022. 

https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antibody-tests-guidelines.html

Articles

As respiratory viruses and COVID-19 variants lurk seemingly everywhere, here’s how best to detect and differentiate.

Crossover symptoms of COVID-19 and influenza

No aspect of pediatric medicine has been as impactful on the health and well-being of our patients and communities as the vaccines that now routinely prevent 16 diseases that were once commonplace.

 Current vaccines include those based on live attenuated viruses (eg, varicella, rotovirus), killed whole organism (eg, rabies, hepatitis A), polysaccharide or native proteins (eg, pneumococcal, meningococcal), and recombinant or whole molecular modification (eg, hepatitis B, herpes zoster).

Today nearly 260 vaccines are in development 

. Many of these are directed at infectious diseases, but many novel vaccines are being developed to treat or prevent allergies, autoimmune disorders, cancers, and even Alzheimer’s disease.

Following the emergence of severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) in 2012, both deadly coronavirus infections, investigators spent subsequent years developing and perfecting innovative vaccines including adenovirus vector vaccines and messenger RNA (mRNA) vaccines. Both vaccine types were rapidly adapted to combat the SARS-CoV-2 pandemic once the Chinese published the genetic sequence of SARS-CoV-2 in January 2020.

 These vaccines instruct cells to manufacture specific antigens—ie, the spike proteins in the case of the SARS-CoV-2 virus—so that the immune system manufactures spike protein antibodies. As of this writing, the United States has deployed 2 mRNA vaccines (Pfizer and Moderna), as well as a genetically engineered adenovirus vector vaccine (Johnson & Johnson). Both vaccine technologies can easily be modified to target a litany of other viruses.

To date, several adenovirus vector vaccines for HIV, Ebola virus, influenza virus, 

 are under human clinical trials, and others are being developed against rabies, dengue virus, and MERS. Currently, mRNA-based vaccines are in development against HIV, rabies, Zika, cytomegalovirus, respiratory syncytial virus (RSV), Ebola, and others.

These vaccine technologies have also shown great promise against several types of cancer. More than 150 clinical trials assessing mRNA vaccines and more than 200 clinical trials involving adenovirus vector vaccines for infectious diseases and cancers are currently ongoing, according to 

. It is even anticipated that a universal flu vaccine based on these technologies will be developed, and it will no longer require seasonal modifications because it will target stable antigens among influenza viruses.

It is also predicted that there will be new vaccines based on virus like particles (VLPs). These are artificial viruses made up of copies of 1 or more viral proteins that self-assemble into nanoparticles. Current VLP vaccines include the hepatitis B vaccine (Energix-B) and the human papillomavirus vaccine (Gardasil). VLP vaccines are also being developed for chikungunya, Japanese encephalitis, yellow fever, Zika, and malaria, among other diseases.

Yet another new type of vaccine— against allergic asthma—is being investigated. Allergic asthma is characterized by mucus secretion, airway eosinophilia, and elevated levels of IgE antibodies and increased levels of cytokines IL-3 and IL-4. Recently, researchers produced an experimental conjugate vaccine against these interleukins that in animal models have shown prolonged reduction of IgE levels, airway hyperresponsiveness, eosinophilia, and mucus production.

Additionally, there are new vaccine delivery systems under development. The most common method of immunizing children to date has been the direct injection of vaccines either intramuscularly or subcutaneously. Several years ago, a live attenuated influenza intranasal vaccine was developed, which has benefited countless needle-phobic children and adults. Now Altimmune has developed an adenovirus-vectored intranasal vaccine, now in phase I clinical trials, that generates a broad IgG, mucosal IgA, and T- cell response to SARS-CoV-2 and is stable at room temperature.

 Altimmune is also in clinical trials for intranasal vaccines for anthrax and influenza.

Several companies are developing a microneedle patch to administer vaccines. The microneedles are impregnated with vaccine that targets immune cells in the dermis.

 Best of all, these are pain free and stable at room temperature. The patch is applied via a preloaded applicator and removed after a few minutes, leaving the vaccine-impregnated tips embedded in the dermis, releasing vaccine over time. These patches are being investigated as a potential alternative to intramuscular vaccines for influenza and COVID-19.

Two more vaccine delivery systems may change the way patients are immunized. An oral vaccine mechanism, Vector-Adjuvant-Antigen Standardized Technology (VAAST), which tar- gets mucosal IgA is being perfected by Vaxart. VAAST has shown promising results for H5N1 influenza, H1N1 influenza, influenza B, norovirus, and RSV. The second is a vaccine capsule filled with nanoparticles, injected subcutaneously, that would slowly release the vaccine over time, potentially eliminating the need for immunization booster doses.

 Enesi Pharma is developing a universal vaccine implant (UVI) using their ImplaVax needle-free delivery device to inject each UVI up to 7 mm into the dermis 

. Preclinical studies have shown this method to be as effective as intramuscular on subcutaneous injections, with less pain associated with injection, according to the company.

Vaccine technologies in development may facilitate a rapid and effective response to new threats and likely will target not only infectious diseases but also allergies, autoimmune conditions, and cancers. Additionally, new vaccine delivery systems will overcome production and storage obstacles that have slowed the response to the COVID-19 pandemic. Pediatricians and parents, recognizing how much vaccines improve the health and well-being of young patients, have much to look forward to.

1. New era of medicine: vaccines. Pharmaceutical Research and Manufacturers of America.Accessed August 23, 2021. 

https://www.phrma.org/en/Media/New-Era-of-Medicine-Vaccines

2. Sah R, Rodriguez-Morales AJ, Jha R, et al. 2020. Complete genome sequence of a 2019 novel coronavirus (SARS-CoV-2) strain isolated in Nepal. 

 2020;9(11):e00169-20. doi:10.1128/MRA.00169-20

3. Garg H, Mehmetoglu-Gurbuz T, Joshi A. Virus Like Particles (VLP) as multivalent vaccine candidate against chikungunya, Japanese encephalitis, yellow fever and zika virus

 2020;10(1):4017. doi:10.1038/s41598-020-61103-1

4. Conde E, Bertrand R, Balbino B, et al. Dual vaccination against IL-4 and IL-13 protects against chronic allergic asthma in mice. 

 2021;12(1):2574. doi:10.1038/s41467-021-22834-5

5. King RG, Silva-Sanchez A, Peel JN, et al. Single-dose intranasal administration of AdCOVID elicits systemic and mucosal immunity against SARS-CoV-2 in mice. 

 Priprint posted online October 11, 2020. doi:10.1101/2020.10.10.331348

6. Li Y, Hu X, Dong Z, et al. Dissolving microneedle arrays with optimized needle geometry for transcutaneous immunization. 

 2020;(151):105361. doi:10.1016/j.ejps.2020.105361

7. Bobbala S, Hook S. Vaccine implants: current status and recent advancements. 

 2020;4(3):319-330. doi:10.1042/ETLS20200164

A look at where vaccine technologies will be going.

The future of vaccinology

The first population-based vaccine registry in the United States was launched in Delaware in 1974. These did not begin to flourish until the Robert Wood Johnson Foundation introduced their “All Kids Count” program in 1991, providing grants to 23 applicants to support the funding of registries. Government funding for immunization registries became available when President Bill Clinton included immunization registries in his Childhood Immunization Initiative in 1993.

There are currently 63 registries, now called immunization information systems (IISs), in the United States. These include state-, island-, and city-based IISs, each operating independently under its respective local and state policies with their own rules around collection and use of data, analysis, and operational routines.

 Figure 1 shows the percentage of children under 6 participating in a state-based IIS as of 2019.

An IIS is a confidential, population-based, computerized database that records all immunization doses administered by participating providers residing within a geographic area. IISs provide a consolidated record of administered vaccines for the benefit of the patient, their family, and the greater public health. An IIS keeps a record of vaccinations given, dates, manufacturing details, and can identify when a future or missed vaccination should be given.

IISs have many advantages; they can improve immunization rates, reduce vaccination errors, identify opportunities to vaccinate, provide epidemiological insights when there is a community outbreak of a vaccine-preventable disease, and allow access by patients, families, schools, and other health care providers. An IIS can also reduce time spent entering data and track vaccine inventory, especially if it is connected through your electronic health record (EHR) system. An IIS can make a child’s immunization portable when the family changes practices, moves from one location to another, or seeks care outside the medical home. (Figure 2)

The administering site is credentialed by the individual IIS under licensed providers who can designate access for data entry and/or viewing by staff. Access to view is allowed for the patient, parents, and specified agencies, such as schools, pharmacies, urgent care facilities, and hospitals. There are federal requirements for documenting vaccines established by the Centers for Disease Control and Prevention (CDC), which includes the specific vaccine, manufacturer, lot number, the date and location, and that the patient and/or family was given a vaccine information statement (VIS) to review with its publication date.

 Most IISs will permit noting if the vaccine was refused and the description of any adverse reactions. Most systems will also identify when a dose of a specific vaccine should be given and have specific time intervals that are not forgiven when a sequential dose is given too early.

It is the responsibility of the administering site to enter the required data and it can be a burden to staff when they need to enter the data in multiple locations, such as the registry, the EHR, and the patient vaccination card. Most pediatric-specific EHRs are certified and connect with a local IIS, requiring only 1 point of data entry that will be shared with the IIS, the medical record, and the patient copy.

There is significant evidence that IISs improve vaccination rates and reduce missed opportunities for administering immunizations. Australia implemented a national IIS in 1996 and demonstrated an increase in full immunization among 2-year-old children from 64% in 1997 to 93% in 2007.

 Australia has a National Health Care System that facilitates implementation and utilization of IISs. Although the United States has yet to implement a national IIS, studies have repeatedly demonstrated that IISs improve vaccination rates, reduce missed opportunities for vaccinations, and facilitate responses to community outbreaks of diseases.

The most significant problem with existing vaccine registries in the United States is the lack of interoperability between them. Relatively few nonpediatric-specific EHRs can currently extract data from local and state registries, or deposit immunization information directly into them. This necessitates office staff performing double entries of immunizations into the office EHR and the local IIS, which is time consuming and unwieldly.

One method of speeding up data entry is the integration of barcode scanning into EHRs (Figure 3). After receiving a shipment of vaccine, the shipment form is scanned into a vaccine inventory, which is integrated into the EHR. When vaccines are ordered for a patient, the barcode on the vial is scanned again and screened by the connected IIS. Warnings appear if the vaccine is being given too soon, not age appropriate, attributed to the wrong funding source (eg, Vaccines for Children Program), or if the vaccine has expired. The staff manually enters the other vaccine administration details into the EHR and the information is electronically sent to the appropriate IIS. Over the next few years, it is anticipated that a growing number of EHRs will have this capability.

There is no uniform rule requiring an administering site to enter that data into the IIS, which further complicates the potential for interoperability. However, the COVID-19 pandemic and the CARES Act may be creating a new opportunity. The law provides funds to support data sharing between EHRs and the IISs. All sites administering COVID-19 vaccines must report all vaccinations into a database that allows for capturing the event and providing reminders for a second dose as indicated by the vaccine given. Can this be another silver lining in the dark skies of the pandemic? We are hopeful; furthermore, it may open the opportunity to connect all vaccine registries into a national database, accessible from anywhere.

1. Freeman VA, DeFriese GH. The challenge and potential of childhood immunization registries. 

. 2003;24:227–246. doi: 10.1146/annurev.publhealth.24.100901.140831

2. For immunization managers. Centers for Disease Control and Prevention. Accessed September 10, 2021. 

https://www.cdc.gov/vaccines/imz-managers/awardee-imz-websites.html

3. Martin DW, Lowery NE, Brand B, Gold R, Horlick G. Immunization information systems: A decade of progress in law and policy. 

. 2015;21(3):296-303. doi:10.1097/PHH.0000000000000040.

4. Groom H, Hopkins DP, Pabst LJ, et al. Immunization information systems to increase vaccination rates: a community guide systematic review. 

. 2015;21(3):227-248. doi:10.1097/PHH.0000000000000069

A look at vaccine registries: what they are, and why they are so crucial.

Russell Libby, MD, FAAP

Articles

Crossover symptoms of COVID-19 and influenza

The future of vaccinology

Immunization information systems: Beyond the basics