What do we know about each of the vaccines’ short-term safety?

Dr K K Aggarwal

President CMAAO, HCFI,

With input from Dr Monica Vasudev

20th January

What do we know about each of the vaccines’ short-term safety?

NEJM Excerpts:

1. Rare events will appear in the news, amplifying attention and worry disproportionate to the actual risk. Our task will be to put these uncommon events into perspective, underscoring that these risks are far lower than the risk of getting sick with Covid-19.

2. These first two vaccines are classified as “reactogenic” — meaning that they will cause some side effects in most people who receive them, reflective of the brisk immune response they generate. In clinical practice, we should put these vaccines in the same side-effect category as the recombinant shingles vaccine (Shingrix) rather than the annual flu vaccine.

3. The most common side effect is pain at the injection site, especially in the 12 to 24 hours after administration. Around 1% of participants in the trials categorized the pain as “severe.” Fatigue and headache are other relatively common side effects; high fevers are less common. These side effects generally resolve within a couple of days and are responsive to acetaminophen or a nonsteroidal antiinflammatory drug such as ibuprofen. In general, side effects are more common in younger vaccine recipients than in older ones, with the second shot inducing more side effects than the first.

4. Bell’s palsy was reported more frequently in vaccine recipients than in controls, but there was not a sufficiently large number of cases to conclude that this was beyond what would naturally be observed in populations of this size by chance.

5. There were no cases of Guillain–Barré syndrome or transverse myelitis.

6. Although hypersensitivity occurred equally in the placebo and vaccine groups in both trials, after distribution of the vaccines in the United Kingdom and the United States, reports emerged of vaccine recipients experiencing severe allergic reactions (anaphylaxis) shortly after receiving their first dose.

7. The current leading suspect in causing these reactions is polyethylene glycol, a compound present in both vaccines. Because of these rare events, administration of the vaccines includes a period of 15 minutes of observation after vaccination — 30 minutes for those with a history of severe allergic reactions of any sort.

8. It’s critically important to emphasize that these allergic reactions are uncommon — the current estimate is that anaphylaxis will occur at approximately 1 in 100,000 doses.

9. Although this rate of severe allergic reactions is higher than that with other vaccines, it is substantially lower than the rate reported with penicillin, which is estimated to be 1 in 5000.

10. Once the vaccine is injected, the mRNA is taken up by the macrophages near the injection site and instructs those cells to make the spike protein. The spike protein then appears on the surface of the macrophages, inducing an immune response that mimics the way we fight off infections and protects us from natural infection with SARS-CoV-2.

11. Enzymes in the body then degrade and dispose of the mRNA. No live virus is involved, and no genetic material enters the nucleus of the cells.

12. Breakthrough insight that put the mRNA inside a lipid coating to prevent it from degrading is quite brilliant

Reactogenicity

Represents the physical manifestation of the inflammatory response to vaccination, and can include injection-site pain, redness, swelling or induration at the injection site, as well as systemic symptoms, such as fever, myalgia, or headache.

Immunogenicity is the ability to induce a humoral and/or cell mediated immune response while reactogenicity is the property of a vaccine of being able to produce excessive immunological responses and associated signs and symptoms.

Both immunogenicity and reactogenicity are sustained by inflammatory reactions (innate immunity). The difference will be at the level (probably nature) of inflammatory reactions involved in both cases. A certain level of inflammatory reactions is needed to sustain a good adaptive immune response, but the excess of these inflammatory reactions will instead impair the same adaptive immune response by creating in some cases serious inflammatory and/or oxidative conditions on basis of immune cell and tissue destruction and associated signs and symptoms (Side effects).

What causes reactogenicity?

1. Vaccines contain antigens that induce an immune response capable of providing specific protection from disease.

2. Individual vaccine antigens induce innate immune responses that may differ qualitatively or quantitatively according to the vaccine composition, but that induce a good adaptive immune response.

3. After entering the body, vaccine antigens are recognised as potential pathogens by conserved pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), pattern-recognition receptors (PRRs) including Toll-like receptors (TLR) that are found on local or peripheral circulating immune cells (e.g. monocytes and macrophages) and on resident stromal cells.

4. The transcription of many target genes is induced in these cells, resulting in the synthesis and release of pyrogenic cytokines (i.e. interleukin [IL]-1, IL-6, tumour necrosis factor-alpha [TNF-α], and prostaglandin-E2) in the bloodstream, that mimics the response to natural infection.

5. Once stimulated, the immune system sets off a complex series of innate immune events that can include phagocytosis, release of inflammatory mediators including chemokines and cytokines, activation of complement, and cellular recruitment.

6. These phenomena are crucial for triggering strong antigen-specific acquired immune responses necessary for protection against disease.

7. These same inflammatory events may also lead to the development of signs and symptoms of injection-site inflammation (pain, redness and swelling) in the vaccinated individual

8. Mediators and products of inflammation in the circulation can affect other body systems to cause systemic side-effects (such as fever, fatigue, and headache).

9. Balancing the beneficial versus the detrimental effects of these inflammatory events is necessary to keep reactogenicity at clinically acceptable levels.

Can prophylactic medications prevent symptoms?

1. A meta-analysis of 13 randomised controlled trials concluded that while prophylactic antipyretics significantly reduced injection-site and systemic symptoms after vaccination, their use was associated with reduced antibody responses to most vaccine antigens.

2. Another recent review concluded that the timing of antipyretic administration was key, because no effect on the antibody response was seen when antipyretics were given as a treatment for symptoms (rather than for prevention of symptoms) after vaccination

3. Because of the need to balance reactogenicity with the potential effect of prophylactic paracetamol on immunogenicity, there are only few vaccines for which prophylactic administration of paracetamol to prevent symptoms is currently actively recommended, usually in situations when different pyrogenic vaccines are co-administered, which results in an additive effect on the incidence of fever. Currently this includes co-administration of Infanrix hexa (GSK) and pneumococcal conjugate vaccines, Infanrix hexa with MMRV vaccines, and of the 4-component meningococcal serogroup B vaccine with routine vaccines.

1. Vaccines, irrespective of their composition, induce some level of inflammation at the injection site within the first hours after their administration which is likely to contribute to causing pain, redness and swelling symptoms.

2. Release of pyrogenic factors into the systemic circulation is thought to stimulate a cascade of immune and nervous system cross-talk that can lead to systemic ‘influenza-like’ symptoms including raised body temperature.

3. There is growing evidence of general associations between systemic inflammatory mediators and systemic symptoms after vaccination. However, no single biomarker of systemic reactogenicity has been identified, but rather a composite of biomarkers; in particular, IL-6, CRP, and for highly immunogenic products, the IFN-signalling pathway, appear to be linked to systemic reactogenicity.

4. To date, it is unknown whether the specific molecular pathways that cause symptoms are independent from pathways involved in the generation of antigen-specific response.

5. Older people display lower systemic levels of IL-6, IL-10 and CRP after vaccination,34 which could contribute to their tendency to report fewer systemic AEs, in particular fever.