9 Feb 2026 Episode 314 Molnupiravir, hybrid immunity, next generation of vaccines

Episode 314

Par 1 The danger of molnupiravir?

Ep 314-1: Theo Sanderson medRxiv 27 Jan 2026 Molnupiravir-associated mutational signature in SARS-CoV-2 sequencing databases

Molnupiravir’s mode of action is inducing hypermutations

The G-to-A “signature” of these mutations increases in worldwide database after widespread use of MOL in 2022

It is also clearly seen in the AGILE clinical trial

Cluster analysis suggests (but did not formally prove) onward transmission of these mutations

Ep 314-2: Nicolas Foutain-Jones medRxiv 20 Dec 2022: Antiviral treatments lead to the rapid accrual of hundreds of SARS-CoV-2 mutations in immunocompromised patients

Within days of treatment with Molnupiravir large number of low-frequency mutations in chronically infected immunocompromised patients: could persist and, in some cases, were fixed in the virus population.

These includes non-synonymous Spike mutations (potentially generating new variants)

and all patients remained persistently PCR positive post-treatment, thus potentially spreading.

Ep 314-3: Ewen Callaway Nature 7 feb summarizes this evidence

Conclusion: Clearly, these observations are suggestive, but not conclusive as to whether Molnupiravir could enhance the risk of novel “evasive” variants. However, the Panoramic trial (Ep 311-9) concluded

Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community. Taken together, widespread use of Molnupiravir in the community (e.g. elderly care homes) seems contra-indicated.

Par 2 Update on hybrid immunity

1. Meta-analysis Jan 2020-June 2022

Ep 314-4: Bobrovitch Lancet Infect Dis Feb 2023: protection against omicron variant (BA.1, BA.2, BA.5) hospitalization and infection

All estimates of protection waned within months against reinfection but remained high and sustained for hospital admission or severe disease.

→ Individuals with hybrid immunity might be able to extend the period before booster vaccinations are needed compared to individuals who have never been infected.

As could be expected: an increasing number of doses of vaccination + previous infection offers increasingly more protection against severe disease and “any infection” than only a previous infection.

2. Hybrid immunity against BA.2

Ep 314-5: Sara Carazo Lancet Infect Dis Jan 2023

In a test-negative control study amongst health care workers, who tested positive for SARS-CoV-2 during BA.2 epidemic (March-June 2022)

Protection against any BA.2 infection (A) and symptomatic BA.2 infection (B).

NI-V1=no previous infection, one vaccine dose. NI-V2=no previous infection, 2 vaccine doses. NI-V3=no previous infection, 3 vaccine doses.

PI-NV=primary infection non-vaccinated. PI-V1=primary infection before one vaccine dose. PI-V2=primary infection before two vaccine doses. PI-V3=primary infection before three vaccine doses.

V1-PI=primary infection after one vaccine dose. V1-PI-V2=primary infection after first but before second vaccine dose. V1-PI-V3=primary infection after first but before second and third vaccine doses.

V2-PI=primary infection after two vaccine doses. V2-PI-V3=primary infection after second but before third vaccine dose. V3-PI=primary infection after three vaccine doses

Conclusion: Protection against BA.2 (re)-infection

Previous omicron BA.1 infection alone was the single most protective factor (risk reduction of 72%),

• three doses of mRNA vaccine in people with no previous infection (46%).
• pre-omicron primary infection alone (38%) or even than

Hybrid immunity conferred by previous omicron BA.1 primary infection plus vaccination increased estimated protection against BA.2 reinfection, similarly to 96% with two or three vaccine doses, and this protection was maintained for at least 5 months after primary infection.

3. Hybrid imunnity against BA.2.75 subvariants

Ep 314-6: Chemaitelly NEJM 2023

Effectiveness of Previous SARS-CoV-2 Infection in Preventing Reinfection, Irrespective of the Presence of Symptoms, with an Omicron BA.2.75 Subvariant

The study was conducted in Qatar between September 10, 2022, and October 18, 2022.

• Previous infections =
  • pre-omicron infections if the positive test result was obtained before the onset of the omicron wave on December 19, 2021,
  • and as omicron infections (BA.1 or BA.2 infections or BA.4 or BA.5 infections) if the positive test result was obtained on or after that date.

Case participants [SARS-CoV-2] positive tests) and controls (persons with negative SARS-CoV-2 tests) were matched exactly according to sex, 10-year age group, nationality, number of coexisting medical conditions, number of vaccine

doses that had been received by the time of the SARS-CoV-2 test, calendar week of testing, method of testing, and reason for testing.

• A pre-omicron infection offers little protection against BA.2.75 subvariant infection, while omicron BA.4/5 offers more protection than BA.1/2 and most protection is by combination of pre-omicron + BA.4/5.
• Vaccination (not clear how many doses), even with pre-omicron infection, offers little protection, but it enhances protection by omicron infection

Implication Possible importance for CH.1.1 and CA.3.2 , which are upcoming BA.2.75 subvariants in Europe and Belgium (see Ep 311).

4. Hybrid immunity and mucosal IgA

Ep 314-7: Markin Lancet Infect Dis Feb 2023 7-month duration of SARS-CoV-2 mucosal immunoglobulin-A responses and protection

Study in triple vaccinated HCW

In (A) Higher nasal mucosal SARS-CoV-2 WT spike immunoglobulin-A (M-IgA) is associated with lower breakthrough infections in triple vaccinated HCW: cumulative incidence of BA.1, BA.2, and BA.5 breakthrough infection over the 8-month follow-up period, stratified on baseline (ie, 5 weeks after third vaccine dose) M-IgA concentrations above or below the 75th percentile. HRs from Cox regression model:

(B) Triple mRNA vaccination alone results in limited M-IgA (23%), but increases with subsequent infection up to 94 %

(C and D) M-IgA remains elevated in those with the strongest hybrid immunity, associated with strong protection against reinfection with BA.5

Par 3 NEXT GENERATION OF VACCINES

Ep 314-8: Ewen Callaway Nature 2 Feb 2026 offers a very didactic overview

Not shown = nasal vaccines (see Ep 298-299) in China and India, but there are no published phase 3 human trials

Overall conclusion:

There is ample evidence now that even updated ‘bivalent” vaccines are running behind of the moving target.

Hybrid immunity is superior to repeated vaccination, but it implies the risk of the first infection of course.

It is obvious that inducing T cell and mucosal immunity by vaccination could make the difference.

The question remains whether any of the novel concepts (including nasal vaccines) will elicit these responses to the same extent and of the same quality as “hybrid immunity”.

Best wishes,

Guido