Wide World of Vaccines

Omicron Part 2 – Booster Needs Confirmed; Omicron Mutations May Attenuate Virulence

Column Editor: Christopher Harrison, MD | Professor of Pediatrics, UMKC School of Medicine | Clinical Professor of Pediatrics, University of Kansas School of Medicine

Israeli booster data. As discussed in earlier columns, because Israel is four to six months ahead of the U.S. in vaccine and booster use, Israeli experiences may predict U.S. Pfizer vaccine effects (Israel almost exclusively uses Pfizer vaccine). During Israel’s Delta wave, those over 60 years old had a confirmed infection rate 11.3-fold (95% CI, 10.4 to 12.3) lower and severe illness rate 19.5-fold (95% CI, 12.9 to 29.5) lower in booster recipients than in those with two doses but not boosters.¹ Now they report similar protection from boosters in over 4 million patients >16 years old against mostly Delta virus up to Oct. 10, 2021.² The infection rate was overall 10-fold lower against Delta virus in the boosted groups.

Bottom line: Boosters significantly reduced Delta infection rates in those over 15 years old, as well as severe disease in those over 39 years old, and deaths in those over 59 years old. Question: Will booster-induced protection hold up over time in an Omicron surge?

Boosters are even more important for Omicron. Neutralizing activity in sera from 40 mostly female health care workers (20 boosted and 20 not boosted) six months after two doses of Pfizer vaccine was marginal (titer = 8) for Delta and below levels expected to be protective for Beta and Omicron.³ Figure 1. Further, the drop in neutralizing capacity compared to the original SARS-CoV-2 strain was 16-fold for Omicron. Figure 2. The good news is that one month after a booster third dose, mean titers rose to more than 100 for Omicron and nearly 1,000 for Delta. That said, the eight-fold reduction compared to the original SARS-CoV-2 is concerning.

As yet unpublished data on the preliminary U.K. Omicron outbreak was presented on a CDC Clinician Outreach and Communication Activity (COCA) call Jan. 12, showing that vaccine effectiveness (VE) of two Pfizer vaccine doses was <5% at five months after the second dose, rising to 67% after a booster dose. That VE dropped to 45% by four months post boost. With Moderna vaccine the post booster VE was 75% dropping to ~60% two months post boost. These data are not the final word, but they reinforce the concept that more boosters (fourth and perhaps fifth doses) are likely to be needed in the next year particularly for high-risk groups, even if newer variants (Pi, Rho, etc.) do not arise.

Duration of Omicron surge – three months? The South Africans are about six weeks ahead of the U.S. in their Omicron surge, so their experience could predict ours. The South African Omicron surge appeared to go past its peak at about 10 weeks. But remember that South Africa differs from the U.S. with lower vaccination rates (only one-third fully vaccinated, 45% with one dose, <10% boosted, but high >80% seropositivity from prior non-Omicron SARS-CoV-2 infection). So, their surge may be less severe/shorter than ours (U.S. ~60% fully vaccinated, 75% with one dose and ~30% boosted, pre-Omicron seropositivity likely ~45%). Nevertheless, South African cases fell from 44,000/day in mid-December (highest since the 2020 start of the pandemic) to 8,000/day by Jan. 13 (still higher than November 2021 pre-Omicron rates). Figure 3, upper panel. Deaths peaked just recently, Figure 3 lower panel, while COVID-19 hospitalizations have dropped about 50% from late December’s peak.

Interestingly, deaths have not increased as much as hospitalizations, as they did in prior variant surges; but death rates lag four weeks behind infection rates. Pre-existing partial cross-immunity from vaccines or prior infections might not have prevented the observed surge in cases and hospitalizations but still might have reduced deaths. Also, treatment has improved greatly lately, so lower death rates compared to prior surges may be due only partially to Omicron causing milder disease. That said, convalescent sera and available monoclonal antibodies (all but sotrovimab) are now known to be ineffective against Omicron. 

Bottom line: We are a little over halfway through what may be a three-month U.S. Omicron surge (hopefully peaking in some areas now (Northeast), but continuing to increase in other areas). But we need to see how long the post-holiday surge lasts and whether children continue to be affected more by Omicron than by prior variants.

Molecular rationale for milder adult Omicron disease. Ex vivo human tissue models of bronchial epithelium and lung tissue show less Omicron replication in lung parenchyma than in respiratory airway epithelium.⁴ Less replication in lung tissue seems due to relative absence in lung tissue of a specific epithelial cell type, transient secretory epithelial (TSE) cell – a cell in a temporary maturation stage in between a mucous-secreting goblet cell and the ciliated cell. In contrast, airway linings have relatively high numbers of TSE cells. TSE cells express a molecule (TMPRSS2) that improves the SARS-CoV-2 spike protein’s ability to attach to ACE2 receptors. Omicron seems less able than Delta to infect cells unless TMPRSS2 is present.⁵ So Omicron clinical disease should produce more injury to the nose and airways compared to lung tissue.

Animal data on mild lung disease. Data from animal studies indicate that the Omicron nasal viral load in mice and hamsters is the same as for the Delta virus, but lung viral loads are 10 times lower for Omicron than Delta.⁶ Lower lung viral load in turn causes less inflammation or injury, producing lower illness severity and death rates, even in the particularly susceptible Syrian hamster. These data seem to mimic U.K. data that suggest Omicron may cause more disease in airways than pulmonary parenchyma, explaining lower overall severity. The preponderance of airway inflammation may also explain the anecdotal pediatric Omicron experience with more airway disease (croup or bronchiolitis-like) than consolidating pneumonia or organ shutdown seen in adults with Delta.

Summary: Two months into the global Omicron surge, severe disease and deaths seem less although infection rates/hospitalizations have skyrocketed. But we should not let our guard down. Even if severe disease and death rates are about 20 times and 50 times less respectively (not proven yet), the 50 times higher infection rates we are seeing mean that the absolute number of deaths and hospitalizations may be similar to Delta, particularly in the unvaccinated, and our health care systems may stay extraordinarily busy until four to six weeks after the Omicron peak (predicted for February). So, we should continue to encourage boosters for those eligible, and vaccines for eligible young children, who seem more likely to need hospitalization for airway disease, such as bronchiolitis and croup.

What does all this mean? We will need to acquire and use ample supplies of antivirals, of Omicron-effective monoclonal antibodies, and of vaccines, including boosters, to get us to a new normal.    

Figure 1. Increased neutralizing titers in Pfizer mRNA vaccine recipients receiving a booster third dose.

Figure 2. Comparison of neutralizing capacity of sera from health care workers receiving two or three doses of Pfizer mRNA vaccine. Less loss of capacity after third (booster) dose and less against Delta variant.

Figure 3. South African Omicron infections/deaths per day. Adapted from the WHO dashboard (https://covid19.who.int/region/afro/country/za). Accessed Jan. 11, 2022.

References:

1. Bar-On YM, Goldberg Y, Mandel M, et al. Protection of BNT162b2 vaccine booster against Covid-19 in Israel. N Engl J Med. 2021;385(15):1393-1400. doi:10.1056/NEJMoa2114255
2. Bar-On YM, Goldberg Y, Mandel M, et al. Protection against Covid-19 by BNT162b2 booster across age groups. N Engl J Med. 2021;385(26):2421-2430. doi:10.1056/NEJMoa2115926
3. Nemet I, Kliker L, Lustig Y, et al. Third BNT162b2 vaccination neutralization of SARS-CoV-2 Omicron infection. N Engl J Med. Published online December 29, 2021:NEJMc2119358. doi:10.1056/NEJMc2119358
4. Chan MCW, Hui KP, Ho J, et al. SARS-CoV-2 Omicron variant replication in human respiratory tract ex vivo. In Review. 2021. doi:10.21203/rs.3.rs-1189219/v1
5. Lukassen S, Chua RL, Trefzer T, et al. SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. EMBO J. 2020;39(10). doi:10.15252/embj.20105114
6. Diamond M, Halfmann P, Maemura T, et al. The SARS-CoV-2 B.1.1.529 Omicron virus causes attenuated infection and disease in mice and hamsters. In Review. 2021. doi:10.21203/rs.3.rs-1211792/v1