Special Topics

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An analysis of the constituents of mRNA vaccines shows that an anaphylactic reaction may be due to several factors which cannot be determined in clinical practice (see Risma 2021). A recent study of three individuals with a history of PEG allergy and three healthy controls found that the BioNTech/Pfizer vaccine induced positive skin tests in PEG allergic patients, whereas traditional PEG skin testing was negative in two of three patients. As an effect could be induced by PEGylated liposomal doxorubicin, the authors suggest that PEGlyated lipids within nanoparticles, and not PEG in its native state, could be a potential trigger of anaphylaxis to the BioNTech/Pfizer vaccine (Troelnikov 2021). However, it may still be possible to safely vaccinate people with allergies to vaccine components after assessing patients who report allergy to a vaccine, injectable medication, or PEG. Consult an allergist who might triage patients into those able to go ahead with vaccination with the routine 15 minutes of observation, those requiring 30 minutes of observation, and those who require skin testing to PEG and polysorbate before vaccination (Glover 2021, Mustafa 2021). The CDC recommends that appropriate medical treatment for severe allergic reactions be immediately available in the event that an acute anaphylactic reaction occurs following administration of an mRNA COVID-19 vaccine (CDC 20201231, CDC 20210303). In particular, persons without contraindications to vaccination who receive an mRNA COVID-19 vaccine should be observed after vaccination for the following time periods: • 30 minutes: Persons with a history of an immediate allergic reaction of any severity to a vaccine or injectable therapy and persons with a history of anaphylaxis due to any cause. • 15 minutes: Everyone else

Post-exposure SARS-CoV-2 vaccination

Could post-exposure vaccination with SARS-CoV-2 vaccines be able to mitigate COVID-19 disease? Claude Muller of the Luxembourg Institute of Health argues that there might be enough time for protective vaccine effects to set in (Muller 2021):

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1. The time from SARS-CoV-2 infection to hospitalization is around two weeks: o Incubation time of SARS-CoV-2 infection: 5 days (Elias 2021) + o Time from symptom onset to hospitalization: around 7 to 10 days 2. Partial protection from mRNA vaccines has been shown as early as two weeks after the first vaccine dose (Polack 2020, Dagan 2021) In particular, individuals with a long incubation period could benefit from post-exposure vaccination. While a large randomized control trial would be needed to demonstrate the efficacy of this approach, post-exposure SARSCoV-2 vaccination would cause no harm and could only benefit the vaccine recipients (Muller 2021). Post-exposure vaccination is not new – protection is quite high in a number of infectious diseases (hepatitis A, 85%; hepatitis B, 85%; measles, 83%; varicella, 67%; smallpox, 45%; and mumps, 38%) (Gallagher 2019).

Current evidence indicates that only one vaccine dose is needed to maximize immune protection in individuals who survived a previous SARS-CoV-2 infection (Manisty 2021, Krammer 2021, Reynolds 2021). In these cases, the prevaccination SARS-CoV-2 infection is analogous to immune priming and the first vaccine dose analogous to the (second) booster injection. It would even seem that protection provided by a previous SARS-CoV-2 infection plus a single BioNTech/Pfizer vaccine dose is superior to ‘No previous COVID-19’ plus two vaccine doses. A high degree of protection provided by 1) a prevaccination SARS-CoV-2 infection plus 2) one vaccine dose has been suggested/shown by: • Antibody titers measured in participants of clinical mRNA vaccine trials (Krammer 2021, Saadat 2021)8. In the Krammer study, no increase in antibody titers was observed in people with pre-vaccination SARS-CoV-2 infection who received the second vaccine dose.

8 In a study by Krammer et al., a single dose of mRNA vaccine in people with a history of SARS-CoV-2 infection (n = 67) elicited post-vaccination antibody titers exceeded the median antibody titers measured in participants without pre-existing immunity after the second vaccine dose (n = 43) by more than a factor of 6 (Krammer 2021) (80% received the Pfizer vaccine and 20% the Moderna vaccine).

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• T and B cell responses after a single dose of the BioNTech/Pfizer vaccine (Reynolds 2021). A single dose showed: o Enhanced T cell immunity o Antibody secreting memory B cell response to spike o Effective neutralizing antibodies against the B.1.1.7 and B.1.351 variants (by comparison, a single vaccine dose without prior infection showed only reduced immunity against variants) • A significant increase of all components of the humoral response with serum neutralizing activities against variants of concern comparable to or greater than neutralizing activity achieved by vaccination of naïve individuals against the historical strain (Wang Z 2021) • A study that measured antibody and memory B cell responses in 33 SARS-CoV-2 naïve and 11 SARS-CoV-2 recovered subjects (Goel 2021) • A study of 500 employees of a 350-bed hospital in Israel (Abu Jabal 2021) • A study of 102 residents from nursing homes in Montpellier, France (Blain 2021) • A study of 124 Italian healthcare professionals (Levi 2021) • A study of SARS-CoV-2 spike-specific T and B cell responses, as well as specific IgA, IgG, IgM and neutralizing antibody titers in 22 individuals in Florence, Italy, 11 of which had a previous history of SARS-CoV-2 infection (Mazzoni 2021) • A study of 51 health-care workers in London (Manisty 2021) A recent preprint reports that T cells from individuals with pre-vaccination SARS-CoV-2 infection differed from those of infection-naive vaccinees (five of the participants had received the BioNTech/Pfizer vaccine and three the Moderna one) (Neidleman 2021). Compared to SARS-CoV-2-naive individuals, previously infected people might even have a superior long-term persistence of nasopharynx-homing SARS-CoV-2-specific T cells. In SARS-CoV-2 recovered individuals, the second vaccine dose often had little effect on the immune response (Goel 2021, Painter 2021). Table 5 presents 6 situations: 1) people with or without previous SARS-CoV-2 infection who 2) receive no, one or two vaccine injections.

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Table 5. Vaccination after previous SARS-CoV-2 infection Scenario Previous SARS-CoV-2 infection? First dose of vaccine Second dose of vaccine Immunology

1 No

2 No

3 No No No No protection Yes No Protection starting around two weeks after the first injection. In one study, 92% of vaccinees (n = 475) had detectable antiSARS-CoV-2 spike IgG three weeks after the first dose of BioNTech/Pfizer (Abu Jabal 2021). Yes Yes Excellent protection (Dagan 2021).

4 Yes No No (Some) protection against future SARS-CoV-2 infection, possibly even against variant strains such as B.1.1.7 and B.1.351 (Reynolds 2021), but protection probably not as good as in Scenario 3. 5 Yes Yes No Rapid antibody response after one dose of either the BioNTech/Pfizer or the Moderna vaccine. Probably even better protection than in Scenario 3. A previous SARSCoV-2 infection is analogous to immune priming – and a single vaccine dose acts as booster injection (Krammer 2021, Abu Jabal 2021, Saadat 2021, Manisty 2021, Goel 2021, Reynolds 2021), even in nursing home residents (Blain 2021). 6 Yes Yes Yes After a previous SARS-CoV-2 infection, a second vaccine injection would seem to offer no additional protection (Goel 2021). Give the second injection to another person.

In summary, people with prior SARS-CoV-2 infections • Benefit from vaccination and should always be vaccinated • Should probably receive only one dose of vaccine o To make this dose available for another individual o To avoid adverse events from the second dose. People with pre-existing immunity may experience systemic side effects such as fatigue, headache, chills, muscle pain, fever, and

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joint pain with considerably higher frequency than people without pre-existing immunity (Krammer 2021). It will be interesting to monitor immunity to natural infection and following vaccination over time and show whether differences in vaccine immune response between previously SARS-CoV-2 infected or SARS-CoV-2 naïve individuals are maintained over time.

Delayed booster injection

The debate about whether delaying the second booster vaccine dose is a risk –“extended prime-boost interval” strategy chosen by the UK to vaccinate a higher percentage of the population quicker and to maximize the number of people who would be partially protected from hospitalization and death –may be about to be settled. In a study of 175 people who were aged over 80 and living independently and who received the BioNTech/Pfizer vaccine, peak antibody levels were 3.5 times higher in those who received the booster dose 12 weeks after the first dose when compared to those who received it after 3 weeks (Parry 2021 – PR1, PR2). Further studies will have to show whether these findings can be repeated in younger people and whether the enhanced immune responses seen after an extended prime-boost interval will help sustain immunity over the longer term.

Two shots, two vaccines

The Com-COV trial compares the four possible prime-boost combinations of the BioNTech/Pfizer vaccine and the AstraZeneca vaccine. The preliminary reactogenicity data show that among the participants who received the boost vaccine 28 days after the first dose, both heterologous vaccine schedules (BioNTech/Pfizer + AstraZeneca or AstraZeneca + BioNTech/Pfizer) induced greater systemic reactogenicity following the boost dose than homologous schedules (BioNTech/Pfizer + BioNTech/Pfizer or AstraZeneca + AstraZeneca); this was accompanied by more frequent use of paracetamol (see Table 6) (Shaw 2021). Most of this increase in reactogenicity was observed in the 48 h after the second dose. The authors of the study suggest that routine prophylactic use of paracetamol could help mitigate these effects. They also note that the participants in this trial were aged 50 years and older and that reactogenicity could be higher in younger individuals. Data about the primary immunological outcome are expected in June.

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Table 6. Feverishness* and paracetamol use after the booster dose in homologous and heterologous vaccine schedules

Prime/Boost (n)

Feverishness Paracetamol use BioNTech/Pfizer + BioNTech/Pfizer 118/117 21% 41% AstraZeneca + AstraZeneca 115/112 10% 36% AstraZeneca + BioNTech/Pfizer 114/110 34% 57% BioNTech/Pfizer + AstraZeneca 115/114 41% 60%

* Defined as a self-reported feeling of feverishness. Similar increases were observed for chills, fatigue, malaise, headache, joint and muscle ache.

The Spanish CombivacS study reported similar results. The study enrolled 673 volunteers who had received a first dose of the AstraZeneca vaccine. After 8 to 12 weeks, 441 individuals received the BioNTech/Pfizer vaccine for their second dose and 232 received a second AstraZeneca injection. In the BioNTech/Pfizer group, the neutralizing antibody titers rose seven-fold, as compared with three-fold in the AstraZeneca group (ISCIII 20210518). Less than 2% of study participants reported severe side effects, mostly headaches, general malaise and muscle pain. In the future, such a vaccination strategy, also known as ‘heterologous prime and boost’, may simplify vaccination campaigns in countries with fluctuating vaccine supplies.

Protection of the non-vaccinated

Preliminary data suggest that vaccinating 82% of a vulnerable nursing home population – while continuing to use face masks and other infection-control measures! – may be highly protective for the remaining 18% of unvaccinated residents (see Table 7). The study included 22,232 residents of 280 nursing homes across 21 US states, 18,242 (82%) of whom received at least one dose of mRNA vaccine (80.4% BioNTech/Pfizer, 19.6% Moderna) and 13,048 of these (71.5%) also received the second dose (White 2021). Most infections were asymptomatic, both in vaccinated and unvaccinated residents.