2 July 2021 Episode 149 Breakthrough infections

Fri, 07/02/2021 - 18:43

Episode 149 : Breakthrough infections after vaccination

Dear colleagues,

I was wondering what the prevalence of breakthrough infections are.  To this end, I first looked after official CDC data (Ep 149-1/2), then  a JCI paper that critically discusses the definition of “breakthrough” (Ep 149-3). 

Ep 149-1: Official CDC report for period 1 January till 30 April 2021.

  • In the total US population (333 million) 355,000 new infections were noted in the last week of April only.  The highest peak was on Jan 8th with 305,000  infections in 1 day.  During that period the daily death rate was between 4462 on Jan 12 and 726 on April 10.
  • Vaccination was rolled out and on 30 April 101 million were fully vaccinated.
  • Over the total of 4 months 10,262 breakthrough infections in fully vaccinated people were reported, of which 73 % symptomatic, 10 % hospitalized (but only 7 % for COVID) and 2 % (160) died
  • In only 5 % of these cases sequencing was done: it revealed 64 % VOC (including the alpha, beta and gamma, but NOT yet delta). This proportion of VOC, however, is similar in the general population.

Two limitations:

  • The reporting is passive, hence a significant underreporting is expected (many a- or pauci-symptomatics are missed)
  • Only 5 % sequenced.

Ep 149-2:  Follow-up on CDC website from 1 May till 21 June: focusing on hospitalization or death only: on 150 million fully vaccinated 4115 breakthroughs: of which 76 % in > 65yrs, with 608 true COVID deaths.

Note: in this paper CDC explicitly recommends vaccination of all people over 12 years old!

Ep 149-3: A viewpoint by John Schiefellin et al. in JCI on the definition of a breakthrough infection.  They argue that a systemic (intramuscular) vaccination is unlikely to protect against upper airway infection (with or without symptoms), but that it should protect against lung (and systemic) disease.  Hence, only people who responded to the vaccine and nevertheless develop lower respiratory infection (LRI) and disease, as evidenced by SARS-CoV-2 PCR+ and radiological signs or low oxygen saturation can be considered breakthrough. See Fig 1:

  • Breakthrough: if PCR+ LRI and disease
    • After good overall vaccine response and reinfection with similar virus
    • After poor overall vaccine response or ineffective response to new variant
  • NO breakthrough: PCR+
    • After good vaccine response and  only upper respiratory symptoms.
    • After NO vaccine response and LRI with disease.  

Obviously, this definition is in line with the CDC policy to count only severe infections (see Ep 149-2), but it also implies that we should only focus on symptomatic disease to calculate vaccine efficacy and breakthrough.  In this way, we could tend to forget the effect of vaccination on transmission. 

Clearly, this strict definition of breakthrough infections is not followed in the following papers.

Let’s first look in health care workers and other rather young and healthy populations.

Ep 149-4 A: The earliest officially published cases, amongst a cohort of 417 HCW in NYC, appeared on April 21 in NEJM.  Two female HCW (51 and 65 yrs), who developed upper respiratory symptoms a few weeks after their second mRNA jab, the symptoms subsided spontaneously. The saliva viral load in the first patient was high (195,000), but low in the second (400). In both cases, several mutations were present in the virus.

Interestingly, the virus of patient 1 carried the E484K mutation, together with others that are also present in the NYC VOC B.1.526 (now referred to as “Iota VOC” see https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/).  In het serum, taken 4 days after signs of infection, high titers of neutralizing Ab were present, including against  E484K and Iota VOC.

These are clear examples of upper respiratory breakthrough infections without LRI. The first patient could certainly have spread infection in view of high viral load.      

Ep 149-4 B: Comments on this case report in NEJM:

  • Douglas Nixon remarks that T cell immunity should be taken into account.
  • Kirtan Rana reports on 506 positive SARS-CoV-2 cases amongst 12,248 HCW in India, Of those, 322 were amongst the 1428 HCW, who were not vaccinated yet, 112 amongst the 7170 who received one dose of the Astra-Zeneca vaccine and 72 in the 3650 who were fully vaccinated, but only 48 of those could be considered as breakthrough infections, because > 14 days after second dose.  Hence a breakthrough prevalence of 1.3 %, versus 22.5 % in unvaccinated or 94 % protection !!! We have no information on disease manifestation nor on sequencing (delta VOC?)

Ep 149-5: Report on an outbreak amongst HCW in Heraklion with the alpha VOC, while most subjects had been vaccinated with Pfizer.  If I read the numbers correctly, the incidence was 33 in 450 unvaccinated HCW (7.3 %), while in vaccinated HCW it was 24 in 1800 (1.3%).  Out of the 24 vaccinated/infected, 21 were fully vaccinated, but we do not know how many of the 1800 were indeed fully vaccinated.

  • This level of protection of about 82 % seems less than what has been reported In Israel, UK en US (> 90 %).
  • Also remarkable: similar viral load in vaccinated and unvaccinated infected HCW.
  • Yet, only in the non-vaccinated group 2 subjects were hospitalized and this group also presented with more fever.

Ep 149-6: Raminez report on breakthrough infection between Feb and May on a university campus, after vaccination with either Pfizer, Moderna or J&J.  In 2551 fully vaccinated subjects, 14 positive PCR (0.55%), versus 1482 infections in 65,877 un-or partly vaccinated (2.25%), hence protection of only 76 %.   It was a systematic testing, so not guided by symptoms.

  • Some breakthroughs had a high viral load.
  • Of the 9 sequenced breakthroughs, 4 were alpha, 2 gamma and 2 delta
  • Ten/14 were women. 
  • Only 1 transmission to close contact
  • Symptoms are not mentioned.

Ep 149-7: Over-representation of VOC and women in 20 breakthrough infections after mRNA vaccination in Washington State.

  • 13 women versus 6 men
  • 15/18 symptomatic, but no hospitalization
  • All were VOC: 8 alpha, 1 beta, 1 gamma and 10 epsilon (B. 1.427/429),  while in the general population 31 % were still non-VOC.   
  • Rather high viral load (median 20 Ct).

Ep 149-8:  Low prevalence of post-vaccination SARS-CoV-2 cases (PVSC) in Californian HCW, no over-representation of VOC.

  • Only 189 PVSC in > 23,000 vaccinated HCW, of which only 23 real breakthrough (> 14 days after 2nd dose of mRNA vaccine).
  • Only 2 hospitalizations: both in PVSC < 14 days after 1st dose.
  • “Presumptive” epsilon VOC was not more represented in vaccinated.
  • Partially and fully vaccinated PVSCs had higher mean Ct values (i.e. lower viral load) than unvaccinated or early post vaccination individuals (27.9 vs 22.9, p<0.001, of n=283 individuals with known Ct value) and were older (mean age 42.3 versus 36.8, p<0.001).

Ep 149-9 A:    Another descriptive study in US military March-May, identifies 24 breakthroughs amongst 1547  SARS-CoV-2 PCR+ subjects (not known how many were vaccinated, but seems very low prevalence). 

  • Half of these 24 were HCW with patient contact, hence more exposed,
  • Mainly men and over a large age range (21-78),
  • Including only one immune-suppressed individual and 8 with co-morbidities.


  • About half had high viral load and from several live virus could be cultivated.
  • Genotyping reveals about 50 % VOC (alpha, gamma epsilon)
  • Three reported severe symptoms, but no hospitalization.   

Ep 149-9 B:  In a very large cohort (> 250,000 mRNA vaccinated people) in US military, only 410 breakthrough infections (> 7 days after the 2nd dose) were found.  Breakthrough was associated with higher age, with White (versus Black) and with anemia (unspecified cause).  No further details. 

Ep 149-10: A carefully matched case-control study in Israel, comparing the genotype of Pfizer vaccine breakthrough infections versus unvaccinated infection at a time period (Jan- early March) that the alpha variant was dominant: 80-90 % in controls and the beta variant was rare (< 1 % in controls).  In this setting,

  • From 14 days after the first dose till 6 days after 2nd: the alpha variant was even more prevalent in cases (89.5 %) than in controls (83.4 %)
  • Between 7-14 days after 2nd dose the beta variant clearly more prevalent in cases (5.4 %) than in controls (0.7 %).
  • From 14 days after 2nd dose: no more prevalence of VOC.  


Special populations

Ep 149-11:  In solid organ transplant patients, under immune suppressive treatment, low antibody and T cell responses after Pfizer vaccination.

Ep 149-12:  An early report on 17 breakthroughs PCR+ after full vaccination of 380 kidney transplant patients (4.4 %)  in Jan-Feb 2021: 7 developed COVID (1.8 %), 4 (57 %) of those were hospitalized and 2 developed severe symptoms, but none died as of April 22. 

Of the 159 non-vaccinated COVID cases over the last year 64 % were hospitalized and 11 (7%) died.   

These preliminary data are difficult to interpret, but they suggest that vaccination in this population with reduced immune responses certainly remains useful.

Ep 149-13:    Also amongst multiple myeloma patients, non-response (or poor response) in antibodies and T cells is common and this paper also describes a fatal case of breakthrough infection in such a patient (under CAR T cell therapy).

Ep 149-14 A and B: two independent papers (of which one from Sciensano and ITM) show very low antibody responses with poor quality (low somatic mutation, low affinity, neutralization) in elderly residents

Ep 149-15:  A large study in 15 skilled nursing home facilities in the Chicago area between Dec 2020 and March 2021 shows that breakthrough infections after full vaccination are rare.  The attack rate was 15%  in unvaccinated and 0.8% in fully vaccinated individuals (95 % protection) , 22 SARS-CoV-2 breakthrough infections were identified among 12 residents and 10 staff members.

  • Two-thirds of infected persons were asymptomatic.
  • A minority experienced mild-to-moderate COVID-19–like symptoms; 2 hospitalizations and one death occurred.
  • No facility-associated secondary transmission was identified.


Ep 149-16: Analysis of emergency care admission in Michigan between Dec and April: 96 % reduction in fully vaccinated subjects, BUT: elderly patients with significant comorbidities remain at high risk for severe outcomes regardless of vaccination status.


Preliminary overall conclusions:


  • Breakthrough infections remained rare after full vaccination: calculated protection between 76 and 95 %;
  • The protection against severe disease seems solid: mainly upper airway symptoms
  • Viral load in nasopharynx can be high and live virus has been recovered, but very little evidence of onwards transmission.
  • Some evidence that mutated viruses and VOC are more prevalent in  breakthrough, but maybe more in partially vaccinated subjects (or those with poor response to full vaccination?)
  • Elderly and immune suppressed individuals more susceptible




  • Most studies in relatively healthy and young populations (HCW, military)
  • Most studies from US
  • By design limited to the first few months after vaccination.
  • Almost no information on Adenovirus vaccines
  • All studies done before the highly infectious delta variant became prevalent.


The big question is what the impact of the delta variant will be on breakthrough infections, especially in elderly and other population with low and probably waning immune responses.


Best wishes,