Building on 'flu shot' success to tackle COVID-19 ​

“Flu shot” provides well-known model for widespread vaccination

The influenza vaccine was first approved for military use in 1945 and deployed to soldiers fighting in World War II. Civilian use was approved the following year. Over the 75 years since, the “flu shot” has become an annual recommended preventative health staple. ~50% of the U.S. population received the flu vaccine last year according to the latest data from the U.S. Centers for Disease Control and Prevention, with the highest vaccination rates consistently being among children and the elderly.

At present, licensed flu vaccines in the U.S. fall into three categories: inactivated influenza virus vaccines (IIV), live, attenuated influenza vaccine (LAIV) and recombinant (protein antigen) influenza virus (RIV). Flu vaccines can be trivalent, being derived from two strains of influenza A virus (IAV H1N1 and IAV H3N2) and one strain of influenza B virus (IBV), or they may be tetravalent, having two strains of IAV and two of IBV to provide broader immune coverage against different strains of influenza virus. Table 1 provides details on some of the influenza vaccine brands commonly distributed in the U.S.

Table 1: Examples of U.S. licensed influenza vaccines

* IM (intramuscular; IN (intranasal); ID (intradermal)
† Recombinant hemagglutinin (HA) proteins produced in a continuous insect cell line (expresSF+^®)
‡ Virus propagated in Madin Darby Canine Kidney (MDCK) cells

The most common type of flu vaccine is the inactivated influenza virus vaccine. Manufacturing it requires dedicated Biosafety Level 2 production facilities where the virus is propagated, isolated by centrifugation and chemically inactivated. The resulting product is then treated with a detergent to disrupt (split) viral particles and enrich for the viral antigens hemagglutinin (HA) and neuraminidase (NA) prior to sterile filtration and packaging.

A robust distribution network for flu vaccine has been established over the years in most developed countries. Dependable supply chains, product stability and lack of specialized equipment required for storage and administration supports widespread availability of flu vaccines in clinical and ad hoc settings such as workplaces, schools, grocery stores and local pharmacies, where they are most commonly administered as a single annual shot.

New considerations for COVID-19 vaccine

There are as of yet no licensed COVID-19 vaccines in the United States; however, a draft landscape of candidate vaccines provided by the World Health Organization (accessed October 2, 2020)¹ shows 42 vaccines in clinical evaluation and an additional 151 candidates in pre-clinical evaluation. Of the 42 clinical candidates, 7 are inactivated vaccines, 13 are subunit, 10 are nucleic acid-based (6 RNA; 4 DNA), 10 are viral-vectored, and 2 are virus-like particle (VLP) vaccines. My previous blog on vaccine technologies includes a detailed synopsis of these vaccine types.

Looking for more information on COVID-19 vaccine development? Read this recent blog for more detail on the mRNA vaccine candidates or the CAS Special Report: Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases recently published in ACS Central Science.

The manufacture of inactivated SARS-CoV-2 vaccines (whole virus and VLP) requires Biosafety Level 3 facilities, and the production of vectored vaccines requires Biosafety Level 2. These facilities are expensive, require a highly trained staff, and utilize processing protocols unique to the virus. Thus, it could take many months to produce a virus product supply sufficient for public health needs.

Like the flu vaccine, the majority of the COVID-19 vaccine candidates also leverage intramuscular administration, requiring patients to receive a shot. Some, however, use alternative routes of administration. Two DNA plasmid vaccine candidates would be administered intradermally, while one vectored candidate is intended to be given orally, one vectored vaccine would be given intranasally and a subunit vaccine is to be delivered subcutaneously.

The various COVID-19 vaccine candidates also differ significantly in key attributes that impact distribution considerations including shelf life, storage requirements and clinical dosing protocols. For example, many vaccines require refrigeration. Thus, their distribution capacity could be governed by the insecurity of cold chain management in some parts of the world. Notably, the ability to formulate biological therapeutics as freeze-dried preparations, requiring less restrictive storage conditions, has improved and may be particularly useful for nucleic acid-based vaccines, including the current mRNA vaccine candidates.

Remaining questions will influence success of global COVID-19 vaccination program

With so many COVID-19 vaccine candidates in the pipeline based on different scientific approaches to generating immunity, it is yet unclear which will offer the optimal combination of efficacy, safety and practical utility to best support widespread use. With many factors to consider, the first candidate approved may not end up being the preferred vaccine platform in the long term.

Beyond the obvious effectiveness and safety criteria, differences in the speed and simplicity of manufacturing may impact the relative adoption of approved vaccines. For example, nucleic acid-based vaccines have been in development for a couple of decades, with a few currently licensed vaccines available in the U.S. targeting the veterinary market. In principle, once the nucleic acid sequence of the desired antigen(s) are known, these types of vaccines obviate the need for upstream processing and present a re-usable platform whose downstream processing can be independent of the encoded gene. This allows for production under less stringent manufacturing guidelines, accelerating progression from R&D through clinical trials to public availability. On the upside, these are scalable technologies that can facilitate rapid vaccine production in crises. On the downside, unlike inactivated or subunit vaccines that can provide a depot of antigen to elicit immunity, nucleic acid vaccines may be subject to immune suppression of antigen expression, metabolic degradation and potential toxicity from novel delivery agents.

Method of administration is another factor that may influence which approved vaccines are most widely adopted, if multiple are approved. It is important to note that SARS-CoV-2, like influenza, is a respiratory virus that must evade the mucosal barrier and local immune response to initiate the infective process. It has been experimentally observed that intramuscular immunization² has a variable effect on the elicitation of mucosal immunity. Recent studies^3-5 on the intranasal administration of SARS-CoV-2 spike protein, both as viral-vectored and subunit vaccines, illustrate that it is possible to reduce pulmonary virus loads, elicit systemic neutralizing antibodies and produce memory T-cells in animal models of COVID-19. Interestingly, there are two mucosal vaccines currently in clinical trials, one intranasal vaccine and one oral vaccine. These will bear watching with regard to efficacy and future development in this area.

Finally, there is the question of durable immunity and susceptibility to re-infection, which will influence how many doses are required to elicit immunity and how frequently vaccination must occur to maintain it. It is certainly clear that neutralizing antibodies correlate to some level of immunity against SARS-CoV-2, but what is not clear is whether that represents the sole protective criteria. There have been reports of patients being diagnosed with COVID-19 infections a second time,⁸ but the implications with regards to protective antibodies and a vaccine are unclear. Influenza vaccines must be given yearly as a result of antigenic drift, that is, the inherent mutability in virus replication that allows for variation in the structure of HA and NA that shields the virus from immune system surveillance. Examination of the mutation of SARS-CoV-2 has shown that most non-synonymous substitutions occur in the nucleocapsid and non-structural protein genes.^6,12 Most concerning is the D614G mutation within the receptor-binding domain of the spike protein that mediates viral entry to respiratory epithelial cells. A preliminary⁷ report demonstrated increased in vitro infectivity and a marginal decrease in serum neutralization of viruses with this mutation. Experimental “universal” vaccines for influenza, which attempt to compensate for virus mutability to avoid the need for re-immunization each year, comprise conserved viral sequences (epitopes) derived from the matrix M2, nucleocapsid (N) and neuraminidase proteins. These have been shown to provide immunity in animal models and a therapeutic effect in human clinical trials.^9-11 Whether this universal approach will be necessary for COVID-19 vaccines is not known.

These are just a few of many factors that will continue to be investigated and considered as approved COVID-19 vaccine candidates enter the market. The successful influenza vaccination program provides a valuable foundation of experience with widespread vaccination that healthcare organizations can build upon to support a successful COVID-19 vaccination effort, but there is always more to learn.

As part of the global scientific community, CAS is committed to leveraging all of our assets and capabilities to support the fight against COVID-19. Check out more CAS COVID-19 resources including scientific insights, open access datasets and special reports.

References:

1. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
2. Fei Su, Girishchandra B. Patel, Songhua Hu & Wangxue Chen (2016) Induction of mucosal immunity through systemic immunization: Phantom or reality?, Human Vaccines & Immunotherapeutics, 12:4, 1070-1079, DOI: 10.1080/21645515.2015.1114195.
3. Ahmed O. Hassan, Natasha M. Kafai, Igor P. Dmitriev, et al. A single intranasal dose of chimpanzee adenovirus-vectored vaccine confers sterilizing immunity against SARS-CoV-2 infection bioRxiv 2020.07.16.205088, DOI: 10.1101/2020.07.16.205088.
4. Min-Wen Ku, Maryline Bourgine, Pierre Authié, et al. Intranasal immunization with a lentiviral vector coding for SARS-CoV-2 spike protein confers vigorous protection in pre-clinical animal models bioRxiv 2020.07.21.214049, DOI: 10.1101/2020.07.21.214049.
5. Xingyue An, Melisa Martinez-Paniagua, Ali Rezvan, et al. Single-dose intranasal vaccination elicits systemic and mucosal immunity against SARS-CoV-2 bioRxiv 2020.07.23.212357, DOI: 10.1101/2020.07.23.212357.
6. Christian Luke D. C. Badua, Karol Ann T. Baldo, Paul Mark B. Medina. Genomic and proteomic mutation landscapes of SARS‐CoV‐2. J Med Virol. 2020; 1‐ 20, DOI: 10.1002/jmv.26548.
7. Jie Hu, Chang-Long He, Qing-Zhu Gao, et al. The D614G mutation of SARS-CoV-2 spike protein enhances viral infectivity and decreases neutralization sensitivity to individual convalescent sera bioRxiv 2020.06.20.161323, DOI: 10.1101/2020.06.20.161323.
8. Akiko Iwasaki. What reinfections mean for COVID-19. The Lancet 2020, DOI: 10.1016/S1473-3099(20)30783-0.
9. Xavier Saelens. The Role of Matrix Protein 2 in the Development of Universal Influenza Vaccines J Infect Dis. 2019:219 (Suppl_1):S68-S74, DOI: 10.1093/infdis/jiz003.
10. Ki-Hye Kim, Yu-Jin Jung, Youri Lee, et al. Cross protection by inactivated influenza viruses containing chimeric hemagglutinin conjugates with a conserved neuraminidase or M2 ectodomain epitope Virology. 2020 (550) 51-60, DOI: 10.1016/j.virol.2020.08.003.
11. Wei J, Li Z, Yang Y, et al. A biomimetic VLP influenza vaccine with interior NP/exterior M2e antigens constructed through a temperature shift-based encapsulation strategy. Vaccine. 2020 Aug 27; 38(38):5987-5996. DOI: 10.1016/j.vaccine.2020.07.015.
12. D Mercatelli, F M Giorgi Geographic and Genomic Distribution of SARS-CoV-2 Mutations. Front. Microbiol. 2020; 11:1800, DOI: 10.3389/fmicb.2020.01800.