22 August Episode 164 (Re) infection after previous infection and/or vaccination

Episode 164 (Re) infection after previous infection and/or vaccination

Epidemiological evidence

Ep 164-1 A: Hanssen in Lancet May 2021 on protection against re-infection during 2020.  According to this huge ( over 4 million) population study, protection by “natural immunity” was over 80 % in those younger than 65 , but only 47 % in those over 65.  Clearly, these data are from a period with no variants and no vaccination.

Ep 164-1 B: A very similar conclusion was reached by Victoria Hall in Lancet, based on the SIREN study in seropositive versus negative HCW in England over the same period (up to Jan 2020): 84% lower risk of re-infection.  

Ep 164-2: Cavanaught MMWR Aug 2021: Case-control amongst almost 750 community residents in Kentucky with previous SARS-CoV-2  infection in 2020, who were re-infected in May-June 2021, the risk was 2.34 times higher in those who were NOT vaccinated versus those who were vaccinated.  Hence vaccination provides an additional layer of protection over “infection-induced immunity”.  Note that the delta variant was not yet dominant in May, but became dominant in June in the US.

Ep 164-3: Kojima medRxiv July 2021:  In a systematic “workforce screening” follow-up of 5306 subjects between May 2020 and July 2021,  258 SARS-CoV-2 infections were observed.  Of those 254 occurred in the 4313 SARS-naive and unvaccinated group, 4 in the 739 mRNA vaccinated and 0 in the 254 previously infected subjects.  The authors conclude that previous infection protects at least equally as vaccination.   Clearly, no data on combined effect of previous infection and vaccination are provided here.

Ep 164-4: Lumley CID July 2021: A follow-up amongst 13 109 HCWs; 8285 received the Pfizer-BioNTech vaccine (1407 two doses), and 2738 the Oxford-AstraZeneca vaccine (49 two doses) in England at the time of the alpha epidemic.  The conclusion is that natural infection resulting in detectable anti-spike antibodies and 2 vaccine doses both provide robust protection against SARS-CoV-2 infection, including against the B.1.1.7 variant.  Fig 2, shows indeed that previous infection + full vaccination has no statistical benefit versus previous infection or full vaccination only. 

Ep 164-5: A similar study published in June in medRxiv amongst 52,000 employees of the Cleveland Clinics also shows no difference in protection between previously infected with or without full mRNA vaccination.

This study started on Dec 16 and ran apparently until May, hence also mostly before the delta surge.

Ep 164-6: Mishra in medRxiv 19 July reports on a telephone research during the delta epidemic in over 2200 subjects, appr 50 % previously found sero-positive and 50 % seronegative for SARS-CoV-2.  In the seropositive group only 3 reported to have contracted the disease again, of whom 1 was hospitalized without needing oxygen, whereas in the previously seronegative group 127 contracted the infection, of whom 30 hospitalized and 12 amongst dose on oxygen.

Very preliminary evidence that natural immunity induced by other variants protects against delta. 

Ep 164-7: Opinion of Kojima and Klausner (authors of Ep 164-2). Their starting point is:

Current recommendations in the United States suggest that people with prior infection should get vaccinated. After all, risk of safe and effective vaccines backfiring on such individuals is virtually zero.

But, based on all the above evidence and the particular US context, they conclude:

… However, in those unwilling or unable—in the United States, this is a large share of the population, however much it might annoy us—there should be an option for medical exemption.

Biological background

Ep 164-8: In a comment on the SIREN study, Florian Krammer emphasizes the need for good “correlates of protection” (still lacking today) and indicates that vaccination mainly induces systemic spike specific antibodies, while natural infection also induces mucosal immunity and T cell responses against other parts of the virus, which may be less prone to “escape mutations”.  This could explain why protection by infection, although maybe associated with weaker spike-Ab, is about as good as vaccine-induced protection.

Ep 164-9:  A detailed longitudinal study of antibody and T cell responses in infected HCW over 6 months in Res Square shows that:

• Asymptomatic infection induces weaker and waning immune responses
• Within subjects with mild disease severa subsets were identified:
  • Some follow the trajectory of weak waning responses of asymptomatics
  • Other have more robust and stable responses, suggesting a better protection.

They conclude:

• Previous infection may not give ongoing protection against VOC months later, and people with asymptomatic infection had lower responses at all time points across many of the immune parameters we measured.
• Maintenance of immune memory over time is critically required for the effective antibody-mediated neutralisation of VOC that is most likely to confer sterilising immunity,
• Other immune mechanisms including non-neutralising antibodies and T cells may account for the protection against severe disease, including for VOC

→ More targeted vaccination program of previously infected individuals may be needed based on early immunological signature 28 days after infection.

(Small cohort, no data on any reinfection).

Ep 164-10: Anichini et al in NEJM April 2021 confirm a finding by others that the neut Ab titers in people with previous infection after 1 dose of mRNA vaccine exceed those after 2 doses in subjects without previous exposure. Ab titers are stable over > 3 months.

Ep 164-11 A: Pegu Science 12 August on durability of vaccine induced responses against VOC

• Moderna elicited antibody activity against SARS-CoV-2 VOC persisted six months after the second dose, albeit at reduced levels compared to Wuhan and D614G,
• More than half of subjects maintaining neutralizing activity against B.1.351 (beta)  at the latest timepoint.

Ep 164-11 B: Moderna published preliminary phase 1 and 2 results of booster mRNA 8 months after primary 2 doses:

• Individuals still had neut titers against D614G (= European variant of 2020), but barely against beta and gamma
• A booster with the original mRNA or a beta-adapted version boosted the responses against both VOC strongly (slightly better with the beta-adapted version). 
•  

Ep 164-12: Tada bioRxiv Aug 2021: Comparison neut after mRNA and Adeno (J&J)

Neut titers against beta, delta, delta plus and lambda after single J&J much lower than after 2 doses of either Pfizer or Moderna → need for a second dose of J&J?  (Questionable whether that will suffice -See next paper)

Ep 164-13:  Very interesting Cell paper showing that

1. Convalescent sera from subjects previously infected with either beta or gamma variant have poor neutralizing activity against delta, but those previously infected with Victoria (S247R) or alpha have very decent neut against delta
2. Neut activity of Pfizer vaccinees is only slightly (2-3 X) decreased against alpha, gamma and delta, but more (7.5 X) decreased against beta.  Astra-Zeneca (2 doses) induces already 3 times lower neut against the Victoria strain (S247R), loses activity against VOC in a relatively similar extent as Pfizer, but it becomes very low in absolute titer

Ep 164-14: Roltgen in medRxiv April 2021 shows that antibodies elicited by mRNA vaccination as compared to infection:

• More IgG than IgM
• Higher titers
• Narrower with regard to recognition of other Coronaviruses
• Similar hierarchy: decreased recognition of alpha, gamma and beta VOC

Ep 164-15: Yadav J Trav Med:  small with limited number of convalescent (after D614G infection) and Covaxin-vaccinated Indian subjects (Covaxin or BBV152 = Indian inactivated vaccine): 3-5 times lower neut titers against beta and delta as compared to B1 (= D614G).  

Some conclusions:

1. Previous infection has a good protective effect (> 80 %), but decreases in 65+ to < 50 %. Preliminary clinical evidence that this holds true for protection against delta VOC?

2. Vaccination certainly boosts neutralzing Ab response in previously infected subjects more than in naïve subjects, but not entirely clear whether that translates in increased clinical protection against infection (especially with delta VOC).

3. Immunological correlates of protection still not established.  Neutralizing Ab tests are good candidatres, but still need for standardization. 

4. Mucosal immunity and T cell responses, alsoy against non-S antigens play a role and are heterogeneous in subjects, recovered from infection, even within one clinical category.

5. All evidence indicates that beta VOC is the most resistant to neut Ab, induced by either infection or vaccination.  Biological advantage of delta rather in fitness characteristics: shorter incubation - higher viral load - longer period of infectiousness (previously discussed).

6. Clear difference in neut Ab against either wild type or VOC induced by mRNA vaccines >> Adenoviruses.  Prelmiminary evidence from inactivated Indian vaccine as well.

7. A booster by wild type vaccine may protect against beta and gamma, but what about delta?